{"gene":"QKI","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"QKI isoforms show distinct subcellular localizations: QKI-5 is restricted to the nucleus, whereas QKI-6 and QKI-7 are localized to the perikaryal cytoplasm. In quakingviable mutants, QKI-6 and QKI-7 are absent exclusively from myelin-forming cells, while QKI-5 is absent only in oligodendrocytes of severely affected tracts, implicating these isoforms as regulators of myelination.","method":"Immunostaining with antibodies raised to unique carboxy peptides of QKI isoforms in mouse nervous system tissue","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by isoform-specific antibodies, replicated across cell types and in genetic mutant model","pmids":["8987822"],"is_preprint":false},{"year":1999,"finding":"QKI isoforms can associate with each other (dimerize), and the QUA1 domain is responsible for QKI self-interaction; a single amino acid change in QUA1 (qkI kt4 lethal mutation) abolishes self-interaction. QKI-5 contains a novel 7-amino acid nuclear localization sequence (STAR-NLS) in its unique C-terminus, and QKI-5 (but not ETLE) shuttles between the nucleus and cytoplasm as shown by interspecies heterokaryon assay.","method":"GFP fusion protein localization, interspecies heterokaryon shuttling assay, mutagenesis of QUA1 domain","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis identifying functional domain, heterokaryon assay for shuttling, GFP localization, multiple orthogonal methods in one study","pmids":["10506177"],"is_preprint":false},{"year":1999,"finding":"QKI-6 functions as a translational repressor by specifically binding to TGE (tra-2 and GLI elements) sequences in 3' UTRs, repressing translation of reporter constructs containing TGEs both in vitro and in vivo. Expression of QKI-6 in C. elegans causes somatic masculinization consistent with repression of tra-2.","method":"In vitro binding assay, in vivo reporter assay in C. elegans, genetic epistasis with tra-3 loss-of-function","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro binding, in vivo reporter, and genetic epistasis with multiple orthogonal approaches","pmids":["10535969"],"is_preprint":false},{"year":2000,"finding":"QKI binds to the 3' UTR of myelin basic protein (MBP) mRNAs and this interaction stabilizes MBP mRNAs. In qkv/qkv mice lacking QKI, isoform-preferential destabilization of MBP mRNAs occurs in the cytoplasm, and MBP mRNAs fail to localize to the myelin membrane fraction, instead accumulating in membrane-free polyribosomes.","method":"RNase protection assay, RNA fractionation, RNA-protein interaction assay, 3'UTR deletion analysis","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct RNA-protein interaction with deletion mapping, fractionation, and in vivo genetic model with multiple readouts","pmids":["10864952"],"is_preprint":false},{"year":2003,"finding":"Tyrosine phosphorylation of QKI by Src family protein tyrosine kinases (Src-PTKs) negatively regulates QKI's interaction with MBP mRNA. During early myelin development, tyrosine phosphorylation of QKI declines, leading to enhanced QKI-MBP mRNA interactions, MBP mRNA accumulation, and accelerated myelinogenesis.","method":"RNA-protein interaction assay, phosphorylation assay, developmental time-course in vivo","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical identification of phosphorylation-dependent RNA binding, in vivo developmental correlation, multiple methods","pmids":["12682013"],"is_preprint":false},{"year":2006,"finding":"QKI binds to the 3' UTR of MAP1B mRNA via QKI response elements, and QKI-deficiency in quakingviable oligodendrocytes results in reduced MAP1B mRNA. RNAi-mediated QKI knockdown destabilizes MAP1B mRNA in CG4 cells, and forced QKI expression promotes MAP1B expression, demonstrating QKI-dependent post-transcriptional stabilization of MAP1B mRNA specifically in oligodendroglia.","method":"RNA immunoprecipitation, RNAi knockdown, forced expression, qkv mutant mice analysis","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function plus direct RNA binding, replicated in cell line and in vivo","pmids":["16855020"],"is_preprint":false},{"year":2006,"finding":"QKI-6 is the predominant isoform responsible for CNS myelination. Transgenic QKI-6 expression specifically in oligodendroglia rescues the severe tremor and hypomyelination of qkV/qkV mutant mice, restores compact myelin with normal lamellar periodicity, and preferentially associates with MBP mRNA to rescue MBP expression. QKI-6 binds PLP mRNA with lower efficiency.","method":"Transgenic rescue experiment, electron microscopy, RNA immunoprecipitation, qkV mutant mice","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic rescue, EM ultrastructure, RNA-protein interaction, multiple orthogonal approaches","pmids":["17079655"],"is_preprint":false},{"year":2007,"finding":"Each QKI isoform (QKI-5, QKI-6, QKI-7) is sufficient to enhance oligodendrocyte progenitor cell (OPC) differentiation with different efficiencies; a point mutation abrogating RNA binding activity abolishes this function. QKI knockdown blocks OPC differentiation and can be partially rescued by QKI-5 and QKI-6 but not QKI-7, indicating differential isoform requirements independent of cell cycle exit.","method":"siRNA knockdown, forced expression, point mutation analysis of RNA-binding domain, OPC differentiation assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function, active-site mutagenesis, isoform specificity established across multiple conditions","pmids":["17575274"],"is_preprint":false},{"year":2009,"finding":"STAR proteins QKI, GLD-1, SAM68, and SLM-2 all recognize bipartite RNA motifs (direct repeats). QKI requires both halves of a bipartite UAAY consensus (SELEX-defined) for high-affinity binding. GLD-1 also binds bipartite RNA sequences from its physiological tra-2 target.","method":"SELEX (Systematic Evolution of Ligands by Exponential enrichment), in vitro binding assays","journal":"BMC Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro SELEX and binding assays defining the bipartite binding motif, single lab but rigorous biochemical method","pmids":["19457263"],"is_preprint":false},{"year":2009,"finding":"QKI-6 and QKI-7 block Schwann cell proliferation and promote Schwann cell differentiation and myelination in PNS co-cultures. Expression of QKI-6 and QKI-7 elevated p27KIP1 and MBP protein levels as markers of Schwann cell differentiation, and QKI-deficient Schwann cells showed reduced MBP, p27KIP1, and Krox-20 mRNAs.","method":"Ectopic expression in dorsal root ganglia co-cultures, electron microscopy, RT-PCR, siRNA knockdown","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function in primary cultures, EM, and loss-of-function with multiple mRNA targets","pmids":["19517016"],"is_preprint":false},{"year":2010,"finding":"QKI-6 decreases the half-life of actin-interacting protein 1 (AIP-1) mRNA by binding to a QKI response element in the AIP-1 3' UTR. During oligodendrocyte differentiation, increased QKI-6 parallels decreased AIP-1 expression; qkv/qkv mice lacking QKI-6/7 show increased AIP-1 in OLs. AIP-1 knockdown causes defects in OL process outgrowth.","method":"2D-DIGE proteomics to identify target, RNA stability assay, QKI response element mapping, qkv mutant mice, siRNA knockdown","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches: proteomics target ID, mRNA stability, in vivo genetic model","pmids":["20631256"],"is_preprint":false},{"year":2010,"finding":"QKI-6 interacts with Argonaute 2 (Ago2) and co-localizes with Ago2 and MBP mRNA in cytoplasmic stress granules of glial cells.","method":"Co-immunoprecipitation, co-localization imaging in glial cells","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus co-localization, single lab, two methods","pmids":["20862255"],"is_preprint":false},{"year":2011,"finding":"SIRT2 abundance in CNS myelin is regulated by a QKI-PLP pathway: in qkv/qkv OL-specific QKI-deficient mice, PLP (but not DM20) mRNA is selectively down-regulated and SIRT2 protein is severely reduced while SIRT2 mRNA remains unaffected. Rescue of SIRT2 expression requires restoration of PLP by QKI-6 expression in oligodendrocytes.","method":"qkv mutant mice analysis, transgenic QKI-6 rescue, QRT-PCR, Western blot","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic rescue and multiple molecular readouts establishing pathway QKI→PLP→SIRT2","pmids":["21948283"],"is_preprint":false},{"year":2011,"finding":"QKI regulates alternative splicing of macroH2A1 pre-mRNA, promoting inclusion of the macroH2A1.1 isoform. RNAi-mediated QKI knockdown increases macroH2A1.1 levels, and QKI expression is significantly reduced in many cancers that show reduced macroH2A1.1 splicing.","method":"RNAi, splicing microarray, RT-PCR validation","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with splicing readout, single lab, correlated with microarray data","pmids":["21844227"],"is_preprint":false},{"year":2011,"finding":"E2F1 directly transcribes QKI by binding to a -542~-538 E2F1 binding site in the QKI promoter (confirmed by ChIP). Increased QKI in turn reduces E2F1 activity and delays S-phase entry, forming a negative feedback loop. QKI overexpression increased p27 and decreased cyclin D1 and c-fos; p27 and c-fos are direct QKI mRNA targets.","method":"Promoter luciferase assay, ChIP, forced expression, cell cycle analysis","journal":"Cell Cycle","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP for direct transcriptional regulation, luciferase reporter, multiple target validations in one study","pmids":["21768773"],"is_preprint":false},{"year":2013,"finding":"QKI-5 and QKI-6, but not QKI-7, inhibit the processing of primary miR-7-1 to mature miR-7 in a QKI response element (QRE)-specific manner. The nuclear QKI isoforms tightly retain pri-miR-7-1 RNA in nuclear foci and keep it associated with Drosha, preventing its processing. QKI-deficient cells show elevated miR-7, reduced EGFR expression, decreased ERK activation, and defects in cell proliferation.","method":"siRNA knockdown, nuclear fractionation, RNA immunoprecipitation, cell proliferation assay, miR-7 inhibitor rescue","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods: RNA pulldown, co-IP with Drosha, nuclear retention imaging, functional rescue","pmids":["23319046"],"is_preprint":false},{"year":2014,"finding":"QKI-5 regulates alternative splicing of NUMB pre-mRNA by binding to two QRE elements, suppressing a pro-proliferative NUMB isoform and thereby preventing activation of the Notch signaling pathway. QKI-5 inhibits splicing by competing with the core splicing factor SF1 for binding to the branchpoint sequence.","method":"RNA binding assay, splicing reporter assay, competing binding with SF1, cell proliferation assay, in vitro and in vivo experiments","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct RNA-protein interaction, competition binding with SF1, in vivo functional assay, pathway placement via Notch signaling","pmids":["24722255"],"is_preprint":false},{"year":2013,"finding":"QKI directly binds the 3' UTR of FOXO1 mRNA and decreases its mRNA stability, resulting in post-transcriptional repression of FOXO1 expression in breast cancer cells. QKI knockdown restores FOXO1 expression; ATRA-induced increase in FOXO1 is dependent on QKI-mediated post-transcriptional regulation.","method":"RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, forced expression","journal":"Oncology Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding demonstrated, mRNA stability assay, pharmacological validation; single lab","pmids":["24398626"],"is_preprint":false},{"year":2016,"finding":"QKI-5 regulates alternative splicing of ADD3 (Adducin 3) exon 14 by binding to multiple sites in an upstream intron region as mapped by iCLIP-seq. QKI-5 binding position determines whether it promotes or represses splicing of target exons. QKI tumor-associated mutations dysregulate splicing of ADD3 and NUMB targets.","method":"iCLIP-seq (nucleotide-resolution in vivo binding), RT-PCR splicing assays, mutagenesis of QKI binding sites, overexpression/knockdown","journal":"Journal of Molecular Cell Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — transcriptome-wide binding map at nucleotide resolution, functional splicing validation, mutagenesis of binding sites","pmids":["33196842"],"is_preprint":false},{"year":2016,"finding":"QKI-5 stabilizes RASA1 mRNA via direct binding to the QKI response element region of RASA1, preventing activation of the Ras-MAPK signaling pathway and suppressing ccRCC cell proliferation.","method":"RNA immunoprecipitation, mRNA stability assay, RASA1 knockdown, cell proliferation assay","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding and mRNA stability assay, pathway rescue with RASA1 knockdown; single lab","pmids":["27767378"],"is_preprint":false},{"year":2016,"finding":"The STAR protein QKI-7 (cytoplasmic isoform) recruits the non-canonical poly(A) polymerase PAPD4 through its unique carboxyl-terminal region to promote cytoplasmic polyadenylation and translation of target mRNAs (hnRNPA1, p27kip1, and β-catenin) in a QKI response element-dependent manner. Only QKI-7, not nuclear isoforms, promotes poly(A) tail extension. An anti-mitogenic signal induces cell cycle arrest at G1 through QKI-7/PAPD4-mediated polyadenylation of p27kip1 mRNA.","method":"Transcriptional pulse-chase analysis, tethered reporter assay, co-immunoprecipitation of QKI-7 and PAPD4, poly(A) length assay, translation assay","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of QKI-7-PAPD4 interaction, poly(A) assay, tethered reporter, multiple targets validated","pmids":["26926106"],"is_preprint":false},{"year":2019,"finding":"QKI-7 uses its C-terminal region to interact with the poly(A) polymerase GLD-2 (PAPD4) and its QUA2 domain to associate with Argonaute 2 (Ago2), thereby recruiting GLD-2 to Ago2. QKI-7 shows specific affinity for miR-122 and significantly promotes GLD-2-mediated 3' adenylation of miR-122 in vitro, stabilizing mature miR-122.","method":"Co-immunoprecipitation, in vitro adenylation assay, QKI isoform-specific knockdown, RNA binding assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of in vitro adenylation, Co-IP for protein interactions, isoform-specific mechanistic dissection","pmids":["31792053"],"is_preprint":false},{"year":2019,"finding":"QKI-6 binds to the HDAC7 intron 1 via the QKI-binding motif upon PDGF-BB stimulation to promote HDAC7 alternative splicing, driving VSMC differentiation from iPSCs. QKI-6 transcriptionally activates SM22 (TAGLN) and QKI-6 knockdown diminishes differentiation capability.","method":"RNA immunoprecipitation, splicing assay, overexpression/knockdown, iPSC differentiation assay, in vivo angiogenesis","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction demonstrated, splicing assay with functional outcome; single lab","pmids":["31331967"],"is_preprint":false},{"year":2019,"finding":"QKI-7 expression in endothelial cells is controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene 6 (TSG-6) as shown by RNA immunoprecipitation and mRNA-decay assays, causing endothelial cell dysfunction in diabetes.","method":"RNA immunoprecipitation (RIP), mRNA-decay assay, QKI-7 knockdown in vivo (hindlimb ischemia mouse model)","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP and mRNA decay assays for direct RNA binding, in vivo knockdown with vascular functional readout","pmids":["32732889"],"is_preprint":false},{"year":2019,"finding":"QKI restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of UCP1 and PGC1α mRNAs. QKI is transcriptionally induced by the cAMP-CREB axis in adipose tissue, and QKI-deficient mice are resistant to high-fat-diet-induced obesity with enhanced thermogenesis.","method":"Adipose tissue-specific QKI knockout mice, mRNA stability assay, nuclear export assay, translation assay, metabolic phenotyping","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse, multiple post-transcriptional mechanisms demonstrated (stability, export, translation), metabolic functional readout","pmids":["31868295"],"is_preprint":false},{"year":2019,"finding":"QKI-5 directly binds the 3' UTR of SOX2 mRNA via QRE elements, reducing SOX2 expression and thereby impairing oral cancer stem cell sphere formation and self-renewal.","method":"RNA immunoprecipitation, QRE deletion/mutation assay, sphere formation assay, in vivo tumor implantation","journal":"Cancer Biology & Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding with cis-element mapping and functional rescue, single lab","pmids":["24918581"],"is_preprint":false},{"year":2020,"finding":"Qki serves as a transcriptional co-activator of the PPARβ-RXRα nuclear receptor complex, controlling transcription of lipid metabolism genes (fatty acid desaturation and elongation). Oligodendrocyte-specific Qki depletion causes rapid demyelination through loss of myelin lipids (monounsaturated and very-long-chain fatty acids) without affecting major myelin proteins; this is rescued by high-fat diet or PPARβ/RXR agonists.","method":"Oligodendrocyte-specific conditional Qki knockout, lipidomic analysis, PPARβ/RXR agonist treatment, in vivo rescue experiment","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotype, pathway rescue by agonists, lipidomics, multiple orthogonal methods","pmids":["32202512"],"is_preprint":false},{"year":2021,"finding":"Qki-5 functions as a co-activator of Srebp2 to control transcription of cholesterol biosynthesis genes in oligodendrocytes, demonstrated by Qki directly interacting with single-stranded DNA and recruiting Srebp2 and RNA Pol II to promoter regions. Qki depletion reduces cholesterol in mouse brain and causes cataract in lens cells; these defects are rescued by topical sterol administration.","method":"ChIP, co-IP of Qki with Srebp2/Pol II, lens-specific and neural stem cell-specific conditional knockout, lipidomic analysis, sterol rescue","journal":"Nature Communications / eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP establishing co-activator function, Co-IP of complex, conditional KO, in vivo rescue; independently supported in two publications","pmids":["34021134","33942715"],"is_preprint":false},{"year":2021,"finding":"Qki in microglia is required for the clearance of myelin debris; microglial Qki deletion impairs phagosome formation and maturation gene splicing and RNA stability. RNA immunoprecipitation confirmed physical interactions between Qki protein and mRNAs of phagocytosis genes including Cd36. Qki depletion in microglia impaired axon integrity, oligodendrocyte maturation, and remyelination.","method":"Microglial conditional Qki knockout, RNA immunoprecipitation, transcriptomic analysis, phagocytosis assay, demyelination model","journal":"The Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with functional assay, RIP for direct RNA binding, multiple cellular readouts","pmids":["33045062"],"is_preprint":false},{"year":2021,"finding":"QKI is indispensable for cardiac sarcomerogenesis through regulation of alternative splicing of genes involved in Z-disc formation and contractile physiology. QKI-deficient hESC-derived cardiomyocytes fail to transition into functional cardiomyocytes; Qki-deficient mouse hearts recapitulate these splicing and structural defects.","method":"CRISPR/Cas9 QKI deletion in hESCs, RNA-seq transcriptomic analysis, Qki-deficient mouse model, sarcomere structural analysis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO in two model systems (hESC and mouse), transcriptomic splicing analysis, functional contractility readout","pmids":["33397958"],"is_preprint":false},{"year":2021,"finding":"QKI deficiency in macrophages promotes RANKL-induced osteoclastogenesis by amplifying NF-κB and MAPK signaling cascades, upregulating NFATc1 activity, and increasing osteoclast-specific markers. Additionally, QKI deficiency inhibits osteoblast formation through inflammatory microenvironment effects.","method":"Monocyte/macrophage-specific QKI knockout mouse, osteoclast differentiation assay, Western blot for NF-κB/MAPK pathways, TRAP staining","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined pathway activation, multiple molecular readouts; single lab","pmids":["32382069"],"is_preprint":false},{"year":2021,"finding":"QKI depletion in macrophages facilitates nuclear export of Keap1 mRNA to the cytoplasm following LPS stimulation, increasing cytoplasmic Keap1 expression and consequently weakening NRF2 nuclear activation and antioxidant capacity. QKI-deficient macrophage mice show amplified oxidative stress and aggravated IBD.","method":"Macrophage-specific QKI knockout mice, shRNA knockdown, nuclear/cytoplasmic fractionation of Keap1 mRNA, DSS-induced colitis model","journal":"Cell Death Discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mRNA localization fractionation assay and in vivo phenotype; single lab","pmids":["33758177"],"is_preprint":false},{"year":2021,"finding":"QKI is a critical regulator of alternative splicing of Integrin Alpha-7 (Itga7) in muscle stem cells. Conditional QKI knockout in MuSCs results in reduced asymmetric cell divisions, loss of myogenic progenitor population, and muscle regeneration defects. Antisense oligonucleotide recapitulating the single QKI-dependent Itga7 splicing event (X1 to X2 shift) impairs Itga7 and Dmd polarization.","method":"Conditional QKI knockout mouse, transcriptomic analysis, antisense oligonucleotide splicing manipulation, asymmetric division assay","journal":"Life Science Alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, transcriptomic validation, antisense oligonucleotide rescue linking single splicing event to functional polarity phenotype","pmids":["35165120"],"is_preprint":false},{"year":2023,"finding":"QKI-7 interacts with stress granule core protein G3BP1 via its C-terminus and shuttles internally m7G-modified mRNAs into stress granules to regulate their stability and translation. QKI proteins selectively recognize internal m7G modifications in mRNAs with a conserved GANGAN motif. QKI7 attenuates translation of Hippo signaling pathway genes, sensitizing cancer cells to chemotherapy.","method":"Transcriptome-wide m7G profiling, QKI binding site mapping, Co-IP of QKI-7 and G3BP1, stress granule imaging, translation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — transcriptome-wide profiling, biochemical Co-IP, functional stress granule imaging, translation assay; rigorous multi-method study","pmids":["37379838"],"is_preprint":false},{"year":2023,"finding":"QKI regulates the alternative splicing of more than 1000 genes in adult cardiomyocytes, including sarcomere, cytoskeletal, calcium-handling, and transcriptional regulators, producing muscle-specific isoforms. Cardiomyocyte-specific QKI deletion causes embryonic lethality and tamoxifen-inducible adult deletion causes rapid heart failure with sarcomere disruption within 7 days. QKI overexpression in neonatal rat ventricular myocytes directs splicing in the opposite direction and enhances contractility.","method":"Conditional cardiomyocyte-specific Cre-Lox knockout, tamoxifen-inducible knockout, RNA-seq, forced overexpression in neonatal cardiomyocytes, contractility measurement","journal":"Cardiovascular Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent conditional KO strategies, transcriptome-wide splicing analysis, gain-of-function with functional contractility readout","pmids":["36627242"],"is_preprint":false},{"year":2024,"finding":"QKI promotes the utilization of the NEAT1 proximal polyadenylation site (PAS) by binding to proximal QKI recognition elements, thereby controlling NEAT1 isoform balance (NEAT1_1 vs NEAT1_2) in glioma cells. CRISPR-Cas9-mediated PAS deletion reduces NEAT1_1 and increases NEAT1_2, enhancing nuclear paraspeckle formation and driving glioma cell migration.","method":"CRISPR-Cas9 PAS deletion, isoform-specific quantification assay, RNA-protein binding assay, transcriptomic analysis, cell migration assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR editing plus RNA binding identification with functional isoform consequences, multiple orthogonal methods","pmids":["39032650"],"is_preprint":false},{"year":2024,"finding":"QKI acts as an auxiliary factor in AGO2/let-7b-mediated gene silencing: QKI depletion decreases AGO2 interaction with let-7b and target mRNA, accelerating target mRNA decay loss. QKI suppresses dissociation of let-7b from AGO2 and slows assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. QKI overexpression suppresses cMYC expression post-transcriptionally and decreases proliferation and migration.","method":"PAR-CLIP, AGO-depleted cell lines, single-molecule imaging, Co-IP of QKI-AGO2, mRNA decay assay, functional proliferation/migration assay","journal":"RNA Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — single-molecule imaging, PAR-CLIP, genetic AGO-depletion, multiple orthogonal biochemical methods","pmids":["38372062"],"is_preprint":false},{"year":2019,"finding":"QKI suppresses scavenger receptor A (SRA) at the transcriptional level by binding to QRE elements in SRA mRNA 3'UTR, reducing lipid uptake in macrophages. miR-29a during monocyte-to-macrophage differentiation directly targets QKI, suppressing QKI and allowing SRA upregulation.","method":"Luciferase reporter assay for 3'UTR binding, QKI overexpression/knockdown, lipid uptake functional assay, miR-29a mimics and inhibitors","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional lipid uptake assay, single lab","pmids":["26056009"],"is_preprint":false},{"year":2014,"finding":"QKI-5 deficiency in diabetic ob/ob myocardium contributes to FoxO1 overactivation; forced QKI-5 expression destabilizes FoxO1 mRNA in cardiomyocytes, reducing FoxO1 protein and subsequent nitrosative and ER stress, thereby reducing ischemia/reperfusion injury.","method":"siRNA and adenovirus-mediated QKI-5 manipulation in vivo (intramyocardial injection), mRNA stability assay, in vivo myocardial I/R model","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with mRNA stability assay and pathway readout; single lab","pmids":["25068621"],"is_preprint":false},{"year":2017,"finding":"QKI regulates transcription of smooth muscle cell genes (SRF, MEF2C, Myocd) through direct binding to their promoters during embryonic stem cell-to-VSMC differentiation. miR-214 targets QKI 3'UTR to suppress QKI expression, thereby de-repressing VSMC gene expression during differentiation.","method":"Luciferase assay for QKI 3'UTR targeting, chromatin binding to promoters, overexpression/knockdown in differentiating ESCs, in vivo differentiation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding assay and luciferase reporter with functional differentiation readout; single lab","pmids":["28186995"],"is_preprint":false},{"year":2020,"finding":"TR4 transcriptionally increases QKI expression to increase circZEB1 levels, which sponges miR-141-3p to increase ZEB1 expression, altering prostate cancer radiosensitivity.","method":"Chromatin immunoprecipitation (ChIP) for TR4 binding to QKI promoter, circRNA quantification, miRNA sponge assay, in vivo PCa mouse model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, in vivo model; single lab, multiple methods","pmids":["32768524"],"is_preprint":false},{"year":2021,"finding":"QKI-5 represses the expressions of Wnt pathway genes Wnt5b, Fzd7, Dvl3, and β-catenin via direct binding to their mRNA specific sites in bone marrow stromal cells, suppressing osteogenic differentiation and activating canonical Wnt pathway.","method":"RIP-seq, RNA FISH, RIP-qPCR, BMSC-specific QKI transgenic and knockout mice, osteogenic differentiation assay","journal":"Archives of Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq for binding targets, FISH for localization, conditional KO mouse; single lab","pmids":["37460362"],"is_preprint":false}],"current_model":"QKI is a STAR family RNA-binding protein with three major isoforms (QKI-5 nuclear, QKI-6 cytoplasmic/nuclear, QKI-7 cytoplasmic) that regulate gene expression post-transcriptionally through multiple mechanisms: it stabilizes or destabilizes target mRNAs (e.g., MBP, MAP1B, RASA1, FoxO1) by binding QKI response elements in 3' UTRs; it regulates alternative splicing of hundreds of targets (NUMB, ADD3, macroH2A1, sarcomeric genes, Itga7) in part by competing with SF1 at branchpoints; it controls miRNA biogenesis by retaining pri-miRNA in the nucleus; it promotes cytoplasmic polyadenylation by recruiting poly(A) polymerases PAPD4/GLD-2 (via QKI-7); it recognizes internal m7G-modified mRNAs and shuttles them into stress granules via G3BP1 interaction; it acts as a transcriptional co-activator of Srebp2 and PPARβ-RXRα complexes to regulate cholesterol and lipid biosynthesis; its RNA-binding activity is negatively regulated by Src-PTK-dependent tyrosine phosphorylation; and it participates in multiple signaling pathways (Notch, Ras-MAPK, NF-κB, Hippo, Wnt) through post-transcriptional control of key pathway mRNAs."},"narrative":{"mechanistic_narrative":"QKI is a STAR-family RNA-binding protein that governs post-transcriptional gene expression across myelination, cell differentiation, metabolism, and tumor biology, expressed as three isoforms with distinct subcellular distributions—nuclear QKI-5, perikaryal QKI-6, and cytoplasmic QKI-7 [PMID:8987822]. QKI proteins self-associate through the QUA1 domain, and QKI-5 carries a dedicated STAR-NLS that drives nucleocytoplasmic shuttling [PMID:10506177], while sequence-specific recognition depends on bipartite UAAY-type QKI response elements (QREs) [PMID:19457263]. Through these elements QKI controls target mRNA fate in opposing directions: it stabilizes transcripts such as MBP and MAP1B [PMID:10864952, PMID:16855020] and destabilizes others including AIP-1, FOXO1, and RASA1 [PMID:20631256, PMID:24398626, PMID:27767378], with MBP-binding activity switched off by Src-PTK tyrosine phosphorylation during myelin development [PMID:12682013]. The isoforms partition mechanistically—nuclear QKI-5/QKI-6 regulate alternative splicing of hundreds of targets (NUMB, ADD3, macroH2A1, Itga7, and sarcomeric genes) in part by competing with the splicing factor SF1 at branchpoints [PMID:24722255, PMID:33196842], and retain pri-miRNAs in nuclear foci with Drosha to block miRNA maturation [PMID:23319046], whereas cytoplasmic QKI-7 recruits the non-canonical poly(A) polymerase PAPD4/GLD-2 to promote cytoplasmic polyadenylation and adenylation of target mRNAs and miR-122 [PMID:26926106, PMID:31792053]. QKI further reads internal m7G-modified mRNAs and shuttles them into stress granules via G3BP1 to tune their translation [PMID:37379838], and modulates AGO2/miRNA-mediated silencing as an auxiliary factor [PMID:38372062]. Beyond RNA, QKI acts on chromatin as a transcriptional co-activator, binding single-stranded promoter DNA to recruit Srebp2 and the PPARβ-RXRα complex to drive cholesterol and lipid biosynthesis required for myelin [PMID:32202512, PMID:34021134, PMID:33942715]. These activities converge on biological programs spanning oligodendrocyte and Schwann cell myelination [PMID:8987822, PMID:17079655, PMID:19517016], microglial myelin-debris clearance [PMID:33045062], cardiac sarcomerogenesis [PMID:33397958, PMID:36627242], muscle stem cell asymmetric division [PMID:35165120], adipose thermogenesis [PMID:31868295], and post-transcriptional control of Notch, Ras-MAPK, NF-κB, and Wnt pathway components [PMID:24722255, PMID:27767378, PMID:32382069, PMID:37460362].","teleology":[{"year":1996,"claim":"Established that QKI is expressed as isoforms with divergent subcellular localizations linked to myelinating cells, framing isoform identity as the basis of functional specialization.","evidence":"Isoform-specific antibody immunostaining in mouse nervous tissue and quaking-viable mutants","pmids":["8987822"],"confidence":"High","gaps":["Did not define the molecular activity of each isoform","Did not identify RNA targets"]},{"year":1999,"claim":"Defined the structural logic of QKI function by mapping self-dimerization to the QUA1 domain and identifying a STAR-NLS that confers QKI-5 nucleocytoplasmic shuttling, explaining the isoforms' differential localization.","evidence":"GFP fusion localization, QUA1 mutagenesis, interspecies heterokaryon shuttling assay","pmids":["10506177"],"confidence":"High","gaps":["Did not establish RNA-binding consequences of dimerization","Shuttling cargo not identified"]},{"year":1999,"claim":"Demonstrated that QKI is a sequence-specific translational repressor acting through 3' UTR elements, providing the first direct functional mechanism.","evidence":"In vitro binding, in vivo C. elegans reporter, genetic epistasis with tra-3","pmids":["10535969"],"confidence":"High","gaps":["Endogenous mammalian targets not yet defined","Repression mechanism at molecular level unresolved"]},{"year":2000,"claim":"Identified MBP mRNA as a physiological QKI target and showed QKI stabilizes and localizes it, connecting QKI molecular activity to the myelination phenotype.","evidence":"RNase protection, RNA fractionation, RNA-protein interaction, 3' UTR deletion in qkv mice","pmids":["10864952"],"confidence":"High","gaps":["Mechanism of mRNA stabilization vs localization not separated","Regulation of QKI binding not addressed"]},{"year":2003,"claim":"Revealed that QKI RNA binding is dynamically controlled by Src-PTK tyrosine phosphorylation, providing a developmental switch for myelin gene expression.","evidence":"RNA-protein interaction and phosphorylation assays with in vivo developmental time-course","pmids":["12682013"],"confidence":"High","gaps":["Specific phosphosites and kinases not fully resolved","Generalizability to non-MBP targets unknown"]},{"year":2006,"claim":"Expanded the target repertoire (MAP1B) and established isoform-specific requirements for oligodendrocyte differentiation, showing RNA-binding is essential for QKI's pro-differentiation function.","evidence":"RIP, RNAi, forced expression, point mutation of RNA-binding domain, transgenic rescue, EM in qkv mice","pmids":["16855020","17079655","17575274"],"confidence":"High","gaps":["Full target set in differentiation undefined","Distinct contributions of stabilization vs splicing not separated"]},{"year":2009,"claim":"Defined the QKI binding motif as bipartite UAAY repeats and extended QKI's myelination role to Schwann cells, generalizing the recognition code across STAR proteins.","evidence":"SELEX and in vitro binding; PNS co-culture gain/loss-of-function with EM","pmids":["19457263","19517016"],"confidence":"High","gaps":["In vivo motif occupancy not mapped","Structural basis of bipartite recognition not resolved"]},{"year":2010,"claim":"Showed QKI can destabilize target mRNAs (AIP-1) and physically associates with Ago2 in stress granules, broadening its repertoire to mRNA decay and RNAi machinery.","evidence":"2D-DIGE proteomics, mRNA stability assay, qkv mice; Co-IP and co-localization with Ago2","pmids":["20631256","20862255"],"confidence":"High","gaps":["Ago2 interaction from single Co-IP without reciprocal validation","Determinants of stabilize-vs-destabilize choice unknown"]},{"year":2011,"claim":"Established QKI as an alternative-splicing regulator and embedded it in a cell-cycle transcriptional circuit (E2F1 feedback) and a QKI→PLP→SIRT2 myelin pathway, broadening function beyond mRNA stability.","evidence":"Splicing microarray/RT-PCR (macroH2A1), ChIP and luciferase (E2F1), genetic rescue (PLP/SIRT2)","pmids":["21844227","21768773","21948283"],"confidence":"High","gaps":["Splicing mechanism not yet mechanistic","Direct vs indirect transcriptional effects not fully separated"]},{"year":2013,"claim":"Uncovered a nuclear-isoform-specific mechanism—retention of pri-miRNA with Drosha to block miRNA biogenesis—and direct 3' UTR repression of FOXO1, linking QKI to EGFR/ERK signaling and cancer.","evidence":"Nuclear fractionation, RIP, Drosha co-IP, miR-7 rescue; RIP and mRNA stability for FOXO1","pmids":["23319046","24398626"],"confidence":"High","gaps":["Generality of pri-miRNA retention beyond miR-7-1 untested","FOXO1 finding single-lab"]},{"year":2014,"claim":"Resolved a splicing mechanism in which QKI-5 competes with SF1 at the branchpoint to control NUMB and gate Notch signaling, and extended 3' UTR control to SOX2 and cardiac FoxO1.","evidence":"Splicing reporter and SF1 competition binding (NUMB); RIP/QRE mapping (SOX2); in vivo I/R model (FoxO1)","pmids":["24722255","24918581","25068621"],"confidence":"High","gaps":["Generality of SF1 competition across targets not established","SOX2 and FoxO1 findings single-lab"]},{"year":2016,"claim":"Defined QKI-7 as the cytoplasmic-polyadenylation isoform via PAPD4/GLD-2 recruitment and mapped transcriptome-wide binding by iCLIP, linking binding position to splicing direction and to Ras-MAPK control via RASA1.","evidence":"Co-IP, poly(A) and tethered reporter assays (QKI-7/PAPD4); iCLIP-seq (ADD3); RIP/stability (RASA1)","pmids":["26926106","33196842","27767378"],"confidence":"High","gaps":["Rules governing position-dependent splicing incompletely defined","RASA1 finding single-lab"]},{"year":2019,"claim":"Established QKI as a chromatin-acting transcriptional co-activator of PPARβ-RXRα and broadened isoform-specific roles to vascular, endothelial, adipose, and lipid-uptake programs.","evidence":"Oligodendrocyte conditional KO with lipidomics and agonist rescue (PPARβ); RIP/splicing (HDAC7), mRNA decay (CD144/NLGN1/TSG-6), conditional KO (UCP1/PGC1α); luciferase (SRA); GLD-2/Ago2 adenylation of miR-122","pmids":["32202512","31331967","32732889","31868295","26056009","31792053","28186995"],"confidence":"High","gaps":["Mechanism of QKI recruitment to nuclear receptor complexes incompletely defined","Several tissue findings single-lab"]},{"year":2021,"claim":"Cemented QKI's dual nucleic-acid roles—single-stranded DNA-binding co-activation of Srebp2 cholesterol biosynthesis and broad splicing/RNA-stability control of cardiac, microglial, muscle, immune, and Wnt programs.","evidence":"ChIP and Co-IP (Srebp2/Pol II) with conditional KO and sterol rescue; conditional KOs and CRISPR in microglia, cardiomyocytes, muscle stem cells, macrophages, and BMSCs with transcriptomic/functional readouts","pmids":["34021134","33942715","33045062","33397958","32382069","33758177","37460362"],"confidence":"High","gaps":["How QKI selects DNA vs RNA targets unresolved","Several lineage phenotypes from single labs"]},{"year":2023,"claim":"Identified QKI as a reader of internal m7G-modified mRNAs that, via G3BP1, routes transcripts into stress granules and reshapes translation, and defined an auxiliary role in AGO2/let-7b silencing.","evidence":"Transcriptome-wide m7G profiling, G3BP1 Co-IP, stress granule imaging, translation assay; PAR-CLIP, AGO-depleted cells, single-molecule imaging","pmids":["37379838","38372062"],"confidence":"High","gaps":["Structural basis of m7G recognition not resolved","Interplay between m7G reading and QRE binding unclear"]},{"year":2024,"claim":"Showed QKI controls alternative polyadenylation site choice to regulate lncRNA isoform balance (NEAT1) and paraspeckle-driven glioma migration, adding 3'-end processing to its mechanistic repertoire.","evidence":"CRISPR-Cas9 PAS deletion, RNA-binding and isoform quantification, migration assay","pmids":["39032650"],"confidence":"High","gaps":["Generality of QKI-directed APA across transcriptome untested","Mechanism linking QKI binding to PAS selection unresolved"]},{"year":null,"claim":"How QKI integrates its many partial mechanisms—choosing among stabilization, destabilization, splicing, polyadenylation, m7G reading, and DNA-binding co-activation at a given target—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model for target-by-target outcome selection","No structural determinant distinguishing DNA vs RNA engagement","Crosstalk between phosphorylation, isoform identity, and partner availability not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,5,8,10,15,16,18,20,24,33,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[26,27,39]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,20,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,20]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[15]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11,33]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,5,15,16,18,20,33,35]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[26,27,39]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24,26,27,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,19,30,41]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,29,32,34]}],"complexes":["stress granule"],"partners":["PAPD4","G3BP1","AGO2","DROSHA","SF1","SREBF2","PPARD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PU8","full_name":"KH domain-containing RNA-binding protein QKI","aliases":["Protein quaking","Hqk","HqkI"],"length_aa":341,"mass_kda":37.7,"function":"RNA reader protein, which recognizes and binds specific RNAs, thereby regulating RNA metabolic processes, such as pre-mRNA splicing, circular RNA (circRNA) formation, mRNA export, mRNA stability and/or translation (PubMed:22398723, PubMed:23630077, PubMed:25768908, PubMed:27029405, PubMed:31331967, PubMed:37379838). Involved in various cellular processes, such as mRNA storage into stress granules, apoptosis, lipid deposition, interferon response, glial cell fate and development (PubMed:25768908, PubMed:31829086, PubMed:34428287, PubMed:37379838). Binds to the 5'-NACUAAY-N(1,20)-UAAY-3' RNA core sequence (PubMed:23630077). Acts as a mRNA modification reader that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Promotes the formation of circular RNAs (circRNAs) during the epithelial to mesenchymal transition and in cardiomyocytes: acts by binding to sites flanking circRNA-forming exons (PubMed:25768908). CircRNAs are produced by back-splicing circularization of pre-mRNAs (PubMed:25768908). Plays a central role in myelinization via 3 distinct mechanisms (PubMed:16641098). First, acts by protecting and promoting stability of target mRNAs such as MBP, SIRT2 and CDKN1B, which promotes oligodendrocyte differentiation (By similarity). Second, participates in mRNA transport by regulating the nuclear export of MBP mRNA (By similarity). Finally, indirectly regulates mRNA splicing of MAG pre-mRNA during oligodendrocyte differentiation by acting as a negative regulator of MAG exon 12 alternative splicing: acts by binding to HNRNPA1 mRNA splicing factor, preventing its translation (By similarity). Involved in microglia differentiation and remyelination by regulating microexon alternative splicing of the Rho GTPase pathway (By similarity). Involved in macrophage differentiation: promotes monocyte differentiation by regulating pre-mRNA splicing in naive peripheral blood monocytes (PubMed:27029405). Acts as an important regulator of muscle development: required for the contractile function of cardiomyocytes by regulating alternative splicing of cardiomyocyte transcripts (By similarity). Acts as a negative regulator of thermogenesis by decreasing stability, nuclear export and translation of mRNAs encoding PPARGC1A and UCP1 (By similarity). Also required for visceral endoderm function and blood vessel development (By similarity). May also play a role in smooth muscle development (PubMed:31331967). In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2 (By similarity) Nuclear isoform that acts as an indirect regulator of mRNA splicing (By similarity). Regulates mRNA splicing of MAG pre-mRNA by inhibiting translation of HNRNPA1 mRNA, thereby preventing MAG exon 12 alternative splicing (By similarity). Involved in oligodendrocyte differentiation by promoting stabilization of SIRT2 mRNA (By similarity). Acts as a negative regulator of the interferon response by binding to MAVS mRNA, downregulating its expression (PubMed:31829086). Also inhibits the interferon response by binding to fibrinectin FN1 pre-mRNA, repressing EDA exon inclusion in FN1 (PubMed:34428287). Delays macrophage differentiation by binding to CSF1R mRNA, promoting its degradation (PubMed:22398723). In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2, promoting SREBF2/SREBP2-dependent cholesterol biosynthesis (By similarity). SREBF2/SREBP2-dependent cholesterol biosynthesis participates to myelinization and is required for eye lens transparency (By similarity) Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation (PubMed:37379838). Acts as a translational repressor for HNRNPA1 and GLI1 (By similarity). Translation inhibition of HNRNPA1 during oligodendrocyte differentiation prevents inclusion of exon 12 in MAG pre-mRNA splicing (By similarity). Involved in astrocyte differentiation by regulating translation of target mRNAs (By similarity) Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G) (PubMed:37379838). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation (PubMed:37379838). Acts as a negative regulator of angiogenesis by binding to mRNAs encoding CDH5, NLGN1 and TNFAIP6, promoting their degradation (PubMed:32732889). Can also induce apoptosis in the cytoplasm (By similarity). Heterodimerization with other isoforms results in nuclear translocation of isoform QKI7 and suppression of apoptosis (By similarity). Also binds some microRNAs: promotes stabilitation of miR-122 by mediating recruitment of poly(A) RNA polymerase TENT2, leading to 3' adenylation and stabilization of miR-122 (PubMed:31792053)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, Stress granule; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96PU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/QKI","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"IGF2BP1","stoichiometry":0.2},{"gene":"TNPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/QKI","total_profiled":1310},"omim":[{"mim_id":"615930","title":"COLORECTAL ADENOCARCINOMA HYPERMETHYLATED GENE, NONCODING; CAHM","url":"https://www.omim.org/entry/615930"},{"mim_id":"609590","title":"QKI, KH DOMAIN-CONTAINING RNA-BINDING PROTEIN; QKI","url":"https://www.omim.org/entry/609590"},{"mim_id":"602968","title":"BRAIN-ENRICHED MYELIN-ASSOCIATED PROTEIN 1; BCAS1","url":"https://www.omim.org/entry/602968"},{"mim_id":"300401","title":"PROTEOLIPID PROTEIN 1; PLP1","url":"https://www.omim.org/entry/300401"},{"mim_id":"159460","title":"MYELIN-ASSOCIATED GLYCOPROTEIN; MAG","url":"https://www.omim.org/entry/159460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":290.1},{"tissue":"tongue","ntpm":207.3}],"url":"https://www.proteinatlas.org/search/QKI"},"hgnc":{"alias_symbol":["QK3"],"prev_symbol":[]},"alphafold":{"accession":"Q96PU8","domains":[{"cath_id":"3.30.1370.10","chopping":"83-185","consensus_level":"high","plddt":91.1746,"start":83,"end":185},{"cath_id":"1.10.12","chopping":"14-60","consensus_level":"high","plddt":82.337,"start":14,"end":60}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PU8-F1-predicted_aligned_error_v6.png","plddt_mean":68.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=QKI","jax_strain_url":"https://www.jax.org/strain/search?query=QKI"},"sequence":{"accession":"Q96PU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PU8"}},"corpus_meta":[{"pmid":"26829751","id":"PMC_26829751","title":"MYB-QKI 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mice.","date":"1996","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8987822","citation_count":149,"is_preprint":false},{"pmid":"37379838","id":"PMC_37379838","title":"QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism.","date":"2023","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/37379838","citation_count":139,"is_preprint":false},{"pmid":"21844227","id":"PMC_21844227","title":"QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21844227","citation_count":132,"is_preprint":false},{"pmid":"30565858","id":"PMC_30565858","title":"LncRNA MEG3 inhibits the progression of prostate cancer by modulating miR-9-5p/QKI-5 axis.","date":"2018","source":"Journal of cellular and molecular 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the cytoplasm.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506177","citation_count":120,"is_preprint":false},{"pmid":"10384037","id":"PMC_10384037","title":"Genomic organization and expression analysis of the mouse qkI locus.","date":"1999","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10384037","citation_count":100,"is_preprint":false},{"pmid":"10535969","id":"PMC_10535969","title":"The STAR protein QKI-6 is a translational repressor.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10535969","citation_count":97,"is_preprint":false},{"pmid":"16342280","id":"PMC_16342280","title":"Human QKI, a new candidate gene for schizophrenia involved in myelination.","date":"2006","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16342280","citation_count":90,"is_preprint":false},{"pmid":"33397958","id":"PMC_33397958","title":"QKI is a critical pre-mRNA alternative splicing regulator of cardiac myofibrillogenesis and contractile function.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33397958","citation_count":87,"is_preprint":false},{"pmid":"17012699","id":"PMC_17012699","title":"The human homolog of the QKI gene affected in the severe dysmyelination \"quaking\" mouse phenotype: downregulated in multiple brain regions in schizophrenia.","date":"2006","source":"The American journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/17012699","citation_count":76,"is_preprint":false},{"pmid":"23319046","id":"PMC_23319046","title":"The QKI-5 and QKI-6 RNA binding proteins regulate the expression of microRNA 7 in glial cells.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23319046","citation_count":73,"is_preprint":false},{"pmid":"14706070","id":"PMC_14706070","title":"Defective smooth muscle development in qkI-deficient mice.","date":"2003","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/14706070","citation_count":69,"is_preprint":false},{"pmid":"27555542","id":"PMC_27555542","title":"A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer.","date":"2016","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27555542","citation_count":67,"is_preprint":false},{"pmid":"19457263","id":"PMC_19457263","title":"The STAR RNA binding proteins GLD-1, QKI, SAM68 and SLM-2 bind bipartite RNA motifs.","date":"2009","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19457263","citation_count":66,"is_preprint":false},{"pmid":"12682013","id":"PMC_12682013","title":"Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12682013","citation_count":66,"is_preprint":false},{"pmid":"31026342","id":"PMC_31026342","title":"QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31026342","citation_count":65,"is_preprint":false},{"pmid":"33237585","id":"PMC_33237585","title":"G protein-coupled oestrogen receptor promotes cell growth of non-small cell lung cancer cells via YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 signalling.","date":"2020","source":"Journal of cellular and molecular 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In quakingviable mutants, QKI-6 and QKI-7 are absent exclusively from myelin-forming cells, while QKI-5 is absent only in oligodendrocytes of severely affected tracts, implicating these isoforms as regulators of myelination.\",\n      \"method\": \"Immunostaining with antibodies raised to unique carboxy peptides of QKI isoforms in mouse nervous system tissue\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by isoform-specific antibodies, replicated across cell types and in genetic mutant model\",\n      \"pmids\": [\"8987822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"QKI isoforms can associate with each other (dimerize), and the QUA1 domain is responsible for QKI self-interaction; a single amino acid change in QUA1 (qkI kt4 lethal mutation) abolishes self-interaction. QKI-5 contains a novel 7-amino acid nuclear localization sequence (STAR-NLS) in its unique C-terminus, and QKI-5 (but not ETLE) shuttles between the nucleus and cytoplasm as shown by interspecies heterokaryon assay.\",\n      \"method\": \"GFP fusion protein localization, interspecies heterokaryon shuttling assay, mutagenesis of QUA1 domain\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis identifying functional domain, heterokaryon assay for shuttling, GFP localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10506177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"QKI-6 functions as a translational repressor by specifically binding to TGE (tra-2 and GLI elements) sequences in 3' UTRs, repressing translation of reporter constructs containing TGEs both in vitro and in vivo. Expression of QKI-6 in C. elegans causes somatic masculinization consistent with repression of tra-2.\",\n      \"method\": \"In vitro binding assay, in vivo reporter assay in C. elegans, genetic epistasis with tra-3 loss-of-function\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro binding, in vivo reporter, and genetic epistasis with multiple orthogonal approaches\",\n      \"pmids\": [\"10535969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"QKI binds to the 3' UTR of myelin basic protein (MBP) mRNAs and this interaction stabilizes MBP mRNAs. In qkv/qkv mice lacking QKI, isoform-preferential destabilization of MBP mRNAs occurs in the cytoplasm, and MBP mRNAs fail to localize to the myelin membrane fraction, instead accumulating in membrane-free polyribosomes.\",\n      \"method\": \"RNase protection assay, RNA fractionation, RNA-protein interaction assay, 3'UTR deletion analysis\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct RNA-protein interaction with deletion mapping, fractionation, and in vivo genetic model with multiple readouts\",\n      \"pmids\": [\"10864952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tyrosine phosphorylation of QKI by Src family protein tyrosine kinases (Src-PTKs) negatively regulates QKI's interaction with MBP mRNA. During early myelin development, tyrosine phosphorylation of QKI declines, leading to enhanced QKI-MBP mRNA interactions, MBP mRNA accumulation, and accelerated myelinogenesis.\",\n      \"method\": \"RNA-protein interaction assay, phosphorylation assay, developmental time-course in vivo\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical identification of phosphorylation-dependent RNA binding, in vivo developmental correlation, multiple methods\",\n      \"pmids\": [\"12682013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"QKI binds to the 3' UTR of MAP1B mRNA via QKI response elements, and QKI-deficiency in quakingviable oligodendrocytes results in reduced MAP1B mRNA. RNAi-mediated QKI knockdown destabilizes MAP1B mRNA in CG4 cells, and forced QKI expression promotes MAP1B expression, demonstrating QKI-dependent post-transcriptional stabilization of MAP1B mRNA specifically in oligodendroglia.\",\n      \"method\": \"RNA immunoprecipitation, RNAi knockdown, forced expression, qkv mutant mice analysis\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function plus direct RNA binding, replicated in cell line and in vivo\",\n      \"pmids\": [\"16855020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"QKI-6 is the predominant isoform responsible for CNS myelination. Transgenic QKI-6 expression specifically in oligodendroglia rescues the severe tremor and hypomyelination of qkV/qkV mutant mice, restores compact myelin with normal lamellar periodicity, and preferentially associates with MBP mRNA to rescue MBP expression. QKI-6 binds PLP mRNA with lower efficiency.\",\n      \"method\": \"Transgenic rescue experiment, electron microscopy, RNA immunoprecipitation, qkV mutant mice\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic rescue, EM ultrastructure, RNA-protein interaction, multiple orthogonal approaches\",\n      \"pmids\": [\"17079655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Each QKI isoform (QKI-5, QKI-6, QKI-7) is sufficient to enhance oligodendrocyte progenitor cell (OPC) differentiation with different efficiencies; a point mutation abrogating RNA binding activity abolishes this function. QKI knockdown blocks OPC differentiation and can be partially rescued by QKI-5 and QKI-6 but not QKI-7, indicating differential isoform requirements independent of cell cycle exit.\",\n      \"method\": \"siRNA knockdown, forced expression, point mutation analysis of RNA-binding domain, OPC differentiation assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function, active-site mutagenesis, isoform specificity established across multiple conditions\",\n      \"pmids\": [\"17575274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STAR proteins QKI, GLD-1, SAM68, and SLM-2 all recognize bipartite RNA motifs (direct repeats). QKI requires both halves of a bipartite UAAY consensus (SELEX-defined) for high-affinity binding. GLD-1 also binds bipartite RNA sequences from its physiological tra-2 target.\",\n      \"method\": \"SELEX (Systematic Evolution of Ligands by Exponential enrichment), in vitro binding assays\",\n      \"journal\": \"BMC Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro SELEX and binding assays defining the bipartite binding motif, single lab but rigorous biochemical method\",\n      \"pmids\": [\"19457263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"QKI-6 and QKI-7 block Schwann cell proliferation and promote Schwann cell differentiation and myelination in PNS co-cultures. Expression of QKI-6 and QKI-7 elevated p27KIP1 and MBP protein levels as markers of Schwann cell differentiation, and QKI-deficient Schwann cells showed reduced MBP, p27KIP1, and Krox-20 mRNAs.\",\n      \"method\": \"Ectopic expression in dorsal root ganglia co-cultures, electron microscopy, RT-PCR, siRNA knockdown\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in primary cultures, EM, and loss-of-function with multiple mRNA targets\",\n      \"pmids\": [\"19517016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"QKI-6 decreases the half-life of actin-interacting protein 1 (AIP-1) mRNA by binding to a QKI response element in the AIP-1 3' UTR. During oligodendrocyte differentiation, increased QKI-6 parallels decreased AIP-1 expression; qkv/qkv mice lacking QKI-6/7 show increased AIP-1 in OLs. AIP-1 knockdown causes defects in OL process outgrowth.\",\n      \"method\": \"2D-DIGE proteomics to identify target, RNA stability assay, QKI response element mapping, qkv mutant mice, siRNA knockdown\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches: proteomics target ID, mRNA stability, in vivo genetic model\",\n      \"pmids\": [\"20631256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"QKI-6 interacts with Argonaute 2 (Ago2) and co-localizes with Ago2 and MBP mRNA in cytoplasmic stress granules of glial cells.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging in glial cells\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus co-localization, single lab, two methods\",\n      \"pmids\": [\"20862255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIRT2 abundance in CNS myelin is regulated by a QKI-PLP pathway: in qkv/qkv OL-specific QKI-deficient mice, PLP (but not DM20) mRNA is selectively down-regulated and SIRT2 protein is severely reduced while SIRT2 mRNA remains unaffected. Rescue of SIRT2 expression requires restoration of PLP by QKI-6 expression in oligodendrocytes.\",\n      \"method\": \"qkv mutant mice analysis, transgenic QKI-6 rescue, QRT-PCR, Western blot\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue and multiple molecular readouts establishing pathway QKI→PLP→SIRT2\",\n      \"pmids\": [\"21948283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"QKI regulates alternative splicing of macroH2A1 pre-mRNA, promoting inclusion of the macroH2A1.1 isoform. RNAi-mediated QKI knockdown increases macroH2A1.1 levels, and QKI expression is significantly reduced in many cancers that show reduced macroH2A1.1 splicing.\",\n      \"method\": \"RNAi, splicing microarray, RT-PCR validation\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with splicing readout, single lab, correlated with microarray data\",\n      \"pmids\": [\"21844227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E2F1 directly transcribes QKI by binding to a -542~-538 E2F1 binding site in the QKI promoter (confirmed by ChIP). Increased QKI in turn reduces E2F1 activity and delays S-phase entry, forming a negative feedback loop. QKI overexpression increased p27 and decreased cyclin D1 and c-fos; p27 and c-fos are direct QKI mRNA targets.\",\n      \"method\": \"Promoter luciferase assay, ChIP, forced expression, cell cycle analysis\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct transcriptional regulation, luciferase reporter, multiple target validations in one study\",\n      \"pmids\": [\"21768773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"QKI-5 and QKI-6, but not QKI-7, inhibit the processing of primary miR-7-1 to mature miR-7 in a QKI response element (QRE)-specific manner. The nuclear QKI isoforms tightly retain pri-miR-7-1 RNA in nuclear foci and keep it associated with Drosha, preventing its processing. QKI-deficient cells show elevated miR-7, reduced EGFR expression, decreased ERK activation, and defects in cell proliferation.\",\n      \"method\": \"siRNA knockdown, nuclear fractionation, RNA immunoprecipitation, cell proliferation assay, miR-7 inhibitor rescue\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods: RNA pulldown, co-IP with Drosha, nuclear retention imaging, functional rescue\",\n      \"pmids\": [\"23319046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"QKI-5 regulates alternative splicing of NUMB pre-mRNA by binding to two QRE elements, suppressing a pro-proliferative NUMB isoform and thereby preventing activation of the Notch signaling pathway. QKI-5 inhibits splicing by competing with the core splicing factor SF1 for binding to the branchpoint sequence.\",\n      \"method\": \"RNA binding assay, splicing reporter assay, competing binding with SF1, cell proliferation assay, in vitro and in vivo experiments\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct RNA-protein interaction, competition binding with SF1, in vivo functional assay, pathway placement via Notch signaling\",\n      \"pmids\": [\"24722255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"QKI directly binds the 3' UTR of FOXO1 mRNA and decreases its mRNA stability, resulting in post-transcriptional repression of FOXO1 expression in breast cancer cells. QKI knockdown restores FOXO1 expression; ATRA-induced increase in FOXO1 is dependent on QKI-mediated post-transcriptional regulation.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, forced expression\",\n      \"journal\": \"Oncology Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding demonstrated, mRNA stability assay, pharmacological validation; single lab\",\n      \"pmids\": [\"24398626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"QKI-5 regulates alternative splicing of ADD3 (Adducin 3) exon 14 by binding to multiple sites in an upstream intron region as mapped by iCLIP-seq. QKI-5 binding position determines whether it promotes or represses splicing of target exons. QKI tumor-associated mutations dysregulate splicing of ADD3 and NUMB targets.\",\n      \"method\": \"iCLIP-seq (nucleotide-resolution in vivo binding), RT-PCR splicing assays, mutagenesis of QKI binding sites, overexpression/knockdown\",\n      \"journal\": \"Journal of Molecular Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — transcriptome-wide binding map at nucleotide resolution, functional splicing validation, mutagenesis of binding sites\",\n      \"pmids\": [\"33196842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"QKI-5 stabilizes RASA1 mRNA via direct binding to the QKI response element region of RASA1, preventing activation of the Ras-MAPK signaling pathway and suppressing ccRCC cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, RASA1 knockdown, cell proliferation assay\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding and mRNA stability assay, pathway rescue with RASA1 knockdown; single lab\",\n      \"pmids\": [\"27767378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The STAR protein QKI-7 (cytoplasmic isoform) recruits the non-canonical poly(A) polymerase PAPD4 through its unique carboxyl-terminal region to promote cytoplasmic polyadenylation and translation of target mRNAs (hnRNPA1, p27kip1, and β-catenin) in a QKI response element-dependent manner. Only QKI-7, not nuclear isoforms, promotes poly(A) tail extension. An anti-mitogenic signal induces cell cycle arrest at G1 through QKI-7/PAPD4-mediated polyadenylation of p27kip1 mRNA.\",\n      \"method\": \"Transcriptional pulse-chase analysis, tethered reporter assay, co-immunoprecipitation of QKI-7 and PAPD4, poly(A) length assay, translation assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of QKI-7-PAPD4 interaction, poly(A) assay, tethered reporter, multiple targets validated\",\n      \"pmids\": [\"26926106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI-7 uses its C-terminal region to interact with the poly(A) polymerase GLD-2 (PAPD4) and its QUA2 domain to associate with Argonaute 2 (Ago2), thereby recruiting GLD-2 to Ago2. QKI-7 shows specific affinity for miR-122 and significantly promotes GLD-2-mediated 3' adenylation of miR-122 in vitro, stabilizing mature miR-122.\",\n      \"method\": \"Co-immunoprecipitation, in vitro adenylation assay, QKI isoform-specific knockdown, RNA binding assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of in vitro adenylation, Co-IP for protein interactions, isoform-specific mechanistic dissection\",\n      \"pmids\": [\"31792053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI-6 binds to the HDAC7 intron 1 via the QKI-binding motif upon PDGF-BB stimulation to promote HDAC7 alternative splicing, driving VSMC differentiation from iPSCs. QKI-6 transcriptionally activates SM22 (TAGLN) and QKI-6 knockdown diminishes differentiation capability.\",\n      \"method\": \"RNA immunoprecipitation, splicing assay, overexpression/knockdown, iPSC differentiation assay, in vivo angiogenesis\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction demonstrated, splicing assay with functional outcome; single lab\",\n      \"pmids\": [\"31331967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI-7 expression in endothelial cells is controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene 6 (TSG-6) as shown by RNA immunoprecipitation and mRNA-decay assays, causing endothelial cell dysfunction in diabetes.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA-decay assay, QKI-7 knockdown in vivo (hindlimb ischemia mouse model)\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP and mRNA decay assays for direct RNA binding, in vivo knockdown with vascular functional readout\",\n      \"pmids\": [\"32732889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of UCP1 and PGC1α mRNAs. QKI is transcriptionally induced by the cAMP-CREB axis in adipose tissue, and QKI-deficient mice are resistant to high-fat-diet-induced obesity with enhanced thermogenesis.\",\n      \"method\": \"Adipose tissue-specific QKI knockout mice, mRNA stability assay, nuclear export assay, translation assay, metabolic phenotyping\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse, multiple post-transcriptional mechanisms demonstrated (stability, export, translation), metabolic functional readout\",\n      \"pmids\": [\"31868295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI-5 directly binds the 3' UTR of SOX2 mRNA via QRE elements, reducing SOX2 expression and thereby impairing oral cancer stem cell sphere formation and self-renewal.\",\n      \"method\": \"RNA immunoprecipitation, QRE deletion/mutation assay, sphere formation assay, in vivo tumor implantation\",\n      \"journal\": \"Cancer Biology & Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding with cis-element mapping and functional rescue, single lab\",\n      \"pmids\": [\"24918581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Qki serves as a transcriptional co-activator of the PPARβ-RXRα nuclear receptor complex, controlling transcription of lipid metabolism genes (fatty acid desaturation and elongation). Oligodendrocyte-specific Qki depletion causes rapid demyelination through loss of myelin lipids (monounsaturated and very-long-chain fatty acids) without affecting major myelin proteins; this is rescued by high-fat diet or PPARβ/RXR agonists.\",\n      \"method\": \"Oligodendrocyte-specific conditional Qki knockout, lipidomic analysis, PPARβ/RXR agonist treatment, in vivo rescue experiment\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined phenotype, pathway rescue by agonists, lipidomics, multiple orthogonal methods\",\n      \"pmids\": [\"32202512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Qki-5 functions as a co-activator of Srebp2 to control transcription of cholesterol biosynthesis genes in oligodendrocytes, demonstrated by Qki directly interacting with single-stranded DNA and recruiting Srebp2 and RNA Pol II to promoter regions. Qki depletion reduces cholesterol in mouse brain and causes cataract in lens cells; these defects are rescued by topical sterol administration.\",\n      \"method\": \"ChIP, co-IP of Qki with Srebp2/Pol II, lens-specific and neural stem cell-specific conditional knockout, lipidomic analysis, sterol rescue\",\n      \"journal\": \"Nature Communications / eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP establishing co-activator function, Co-IP of complex, conditional KO, in vivo rescue; independently supported in two publications\",\n      \"pmids\": [\"34021134\", \"33942715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Qki in microglia is required for the clearance of myelin debris; microglial Qki deletion impairs phagosome formation and maturation gene splicing and RNA stability. RNA immunoprecipitation confirmed physical interactions between Qki protein and mRNAs of phagocytosis genes including Cd36. Qki depletion in microglia impaired axon integrity, oligodendrocyte maturation, and remyelination.\",\n      \"method\": \"Microglial conditional Qki knockout, RNA immunoprecipitation, transcriptomic analysis, phagocytosis assay, demyelination model\",\n      \"journal\": \"The Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with functional assay, RIP for direct RNA binding, multiple cellular readouts\",\n      \"pmids\": [\"33045062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI is indispensable for cardiac sarcomerogenesis through regulation of alternative splicing of genes involved in Z-disc formation and contractile physiology. QKI-deficient hESC-derived cardiomyocytes fail to transition into functional cardiomyocytes; Qki-deficient mouse hearts recapitulate these splicing and structural defects.\",\n      \"method\": \"CRISPR/Cas9 QKI deletion in hESCs, RNA-seq transcriptomic analysis, Qki-deficient mouse model, sarcomere structural analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO in two model systems (hESC and mouse), transcriptomic splicing analysis, functional contractility readout\",\n      \"pmids\": [\"33397958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI deficiency in macrophages promotes RANKL-induced osteoclastogenesis by amplifying NF-κB and MAPK signaling cascades, upregulating NFATc1 activity, and increasing osteoclast-specific markers. Additionally, QKI deficiency inhibits osteoblast formation through inflammatory microenvironment effects.\",\n      \"method\": \"Monocyte/macrophage-specific QKI knockout mouse, osteoclast differentiation assay, Western blot for NF-κB/MAPK pathways, TRAP staining\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined pathway activation, multiple molecular readouts; single lab\",\n      \"pmids\": [\"32382069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI depletion in macrophages facilitates nuclear export of Keap1 mRNA to the cytoplasm following LPS stimulation, increasing cytoplasmic Keap1 expression and consequently weakening NRF2 nuclear activation and antioxidant capacity. QKI-deficient macrophage mice show amplified oxidative stress and aggravated IBD.\",\n      \"method\": \"Macrophage-specific QKI knockout mice, shRNA knockdown, nuclear/cytoplasmic fractionation of Keap1 mRNA, DSS-induced colitis model\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mRNA localization fractionation assay and in vivo phenotype; single lab\",\n      \"pmids\": [\"33758177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI is a critical regulator of alternative splicing of Integrin Alpha-7 (Itga7) in muscle stem cells. Conditional QKI knockout in MuSCs results in reduced asymmetric cell divisions, loss of myogenic progenitor population, and muscle regeneration defects. Antisense oligonucleotide recapitulating the single QKI-dependent Itga7 splicing event (X1 to X2 shift) impairs Itga7 and Dmd polarization.\",\n      \"method\": \"Conditional QKI knockout mouse, transcriptomic analysis, antisense oligonucleotide splicing manipulation, asymmetric division assay\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, transcriptomic validation, antisense oligonucleotide rescue linking single splicing event to functional polarity phenotype\",\n      \"pmids\": [\"35165120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"QKI-7 interacts with stress granule core protein G3BP1 via its C-terminus and shuttles internally m7G-modified mRNAs into stress granules to regulate their stability and translation. QKI proteins selectively recognize internal m7G modifications in mRNAs with a conserved GANGAN motif. QKI7 attenuates translation of Hippo signaling pathway genes, sensitizing cancer cells to chemotherapy.\",\n      \"method\": \"Transcriptome-wide m7G profiling, QKI binding site mapping, Co-IP of QKI-7 and G3BP1, stress granule imaging, translation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — transcriptome-wide profiling, biochemical Co-IP, functional stress granule imaging, translation assay; rigorous multi-method study\",\n      \"pmids\": [\"37379838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"QKI regulates the alternative splicing of more than 1000 genes in adult cardiomyocytes, including sarcomere, cytoskeletal, calcium-handling, and transcriptional regulators, producing muscle-specific isoforms. Cardiomyocyte-specific QKI deletion causes embryonic lethality and tamoxifen-inducible adult deletion causes rapid heart failure with sarcomere disruption within 7 days. QKI overexpression in neonatal rat ventricular myocytes directs splicing in the opposite direction and enhances contractility.\",\n      \"method\": \"Conditional cardiomyocyte-specific Cre-Lox knockout, tamoxifen-inducible knockout, RNA-seq, forced overexpression in neonatal cardiomyocytes, contractility measurement\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent conditional KO strategies, transcriptome-wide splicing analysis, gain-of-function with functional contractility readout\",\n      \"pmids\": [\"36627242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"QKI promotes the utilization of the NEAT1 proximal polyadenylation site (PAS) by binding to proximal QKI recognition elements, thereby controlling NEAT1 isoform balance (NEAT1_1 vs NEAT1_2) in glioma cells. CRISPR-Cas9-mediated PAS deletion reduces NEAT1_1 and increases NEAT1_2, enhancing nuclear paraspeckle formation and driving glioma cell migration.\",\n      \"method\": \"CRISPR-Cas9 PAS deletion, isoform-specific quantification assay, RNA-protein binding assay, transcriptomic analysis, cell migration assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR editing plus RNA binding identification with functional isoform consequences, multiple orthogonal methods\",\n      \"pmids\": [\"39032650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"QKI acts as an auxiliary factor in AGO2/let-7b-mediated gene silencing: QKI depletion decreases AGO2 interaction with let-7b and target mRNA, accelerating target mRNA decay loss. QKI suppresses dissociation of let-7b from AGO2 and slows assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. QKI overexpression suppresses cMYC expression post-transcriptionally and decreases proliferation and migration.\",\n      \"method\": \"PAR-CLIP, AGO-depleted cell lines, single-molecule imaging, Co-IP of QKI-AGO2, mRNA decay assay, functional proliferation/migration assay\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — single-molecule imaging, PAR-CLIP, genetic AGO-depletion, multiple orthogonal biochemical methods\",\n      \"pmids\": [\"38372062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QKI suppresses scavenger receptor A (SRA) at the transcriptional level by binding to QRE elements in SRA mRNA 3'UTR, reducing lipid uptake in macrophages. miR-29a during monocyte-to-macrophage differentiation directly targets QKI, suppressing QKI and allowing SRA upregulation.\",\n      \"method\": \"Luciferase reporter assay for 3'UTR binding, QKI overexpression/knockdown, lipid uptake functional assay, miR-29a mimics and inhibitors\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional lipid uptake assay, single lab\",\n      \"pmids\": [\"26056009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"QKI-5 deficiency in diabetic ob/ob myocardium contributes to FoxO1 overactivation; forced QKI-5 expression destabilizes FoxO1 mRNA in cardiomyocytes, reducing FoxO1 protein and subsequent nitrosative and ER stress, thereby reducing ischemia/reperfusion injury.\",\n      \"method\": \"siRNA and adenovirus-mediated QKI-5 manipulation in vivo (intramyocardial injection), mRNA stability assay, in vivo myocardial I/R model\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with mRNA stability assay and pathway readout; single lab\",\n      \"pmids\": [\"25068621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"QKI regulates transcription of smooth muscle cell genes (SRF, MEF2C, Myocd) through direct binding to their promoters during embryonic stem cell-to-VSMC differentiation. miR-214 targets QKI 3'UTR to suppress QKI expression, thereby de-repressing VSMC gene expression during differentiation.\",\n      \"method\": \"Luciferase assay for QKI 3'UTR targeting, chromatin binding to promoters, overexpression/knockdown in differentiating ESCs, in vivo differentiation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding assay and luciferase reporter with functional differentiation readout; single lab\",\n      \"pmids\": [\"28186995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TR4 transcriptionally increases QKI expression to increase circZEB1 levels, which sponges miR-141-3p to increase ZEB1 expression, altering prostate cancer radiosensitivity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for TR4 binding to QKI promoter, circRNA quantification, miRNA sponge assay, in vivo PCa mouse model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"32768524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI-5 represses the expressions of Wnt pathway genes Wnt5b, Fzd7, Dvl3, and β-catenin via direct binding to their mRNA specific sites in bone marrow stromal cells, suppressing osteogenic differentiation and activating canonical Wnt pathway.\",\n      \"method\": \"RIP-seq, RNA FISH, RIP-qPCR, BMSC-specific QKI transgenic and knockout mice, osteogenic differentiation assay\",\n      \"journal\": \"Archives of Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq for binding targets, FISH for localization, conditional KO mouse; single lab\",\n      \"pmids\": [\"37460362\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"QKI is a STAR family RNA-binding protein with three major isoforms (QKI-5 nuclear, QKI-6 cytoplasmic/nuclear, QKI-7 cytoplasmic) that regulate gene expression post-transcriptionally through multiple mechanisms: it stabilizes or destabilizes target mRNAs (e.g., MBP, MAP1B, RASA1, FoxO1) by binding QKI response elements in 3' UTRs; it regulates alternative splicing of hundreds of targets (NUMB, ADD3, macroH2A1, sarcomeric genes, Itga7) in part by competing with SF1 at branchpoints; it controls miRNA biogenesis by retaining pri-miRNA in the nucleus; it promotes cytoplasmic polyadenylation by recruiting poly(A) polymerases PAPD4/GLD-2 (via QKI-7); it recognizes internal m7G-modified mRNAs and shuttles them into stress granules via G3BP1 interaction; it acts as a transcriptional co-activator of Srebp2 and PPARβ-RXRα complexes to regulate cholesterol and lipid biosynthesis; its RNA-binding activity is negatively regulated by Src-PTK-dependent tyrosine phosphorylation; and it participates in multiple signaling pathways (Notch, Ras-MAPK, NF-κB, Hippo, Wnt) through post-transcriptional control of key pathway mRNAs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"QKI is a STAR-family RNA-binding protein that governs post-transcriptional gene expression across myelination, cell differentiation, metabolism, and tumor biology, expressed as three isoforms with distinct subcellular distributions—nuclear QKI-5, perikaryal QKI-6, and cytoplasmic QKI-7 [#0]. QKI proteins self-associate through the QUA1 domain, and QKI-5 carries a dedicated STAR-NLS that drives nucleocytoplasmic shuttling [#1], while sequence-specific recognition depends on bipartite UAAY-type QKI response elements (QREs) [#8]. Through these elements QKI controls target mRNA fate in opposing directions: it stabilizes transcripts such as MBP and MAP1B [#3, #5] and destabilizes others including AIP-1, FOXO1, and RASA1 [#10, #17, #19], with MBP-binding activity switched off by Src-PTK tyrosine phosphorylation during myelin development [#4]. The isoforms partition mechanistically—nuclear QKI-5/QKI-6 regulate alternative splicing of hundreds of targets (NUMB, ADD3, macroH2A1, Itga7, and sarcomeric genes) in part by competing with the splicing factor SF1 at branchpoints [#16, #18], and retain pri-miRNAs in nuclear foci with Drosha to block miRNA maturation [#15], whereas cytoplasmic QKI-7 recruits the non-canonical poly(A) polymerase PAPD4/GLD-2 to promote cytoplasmic polyadenylation and adenylation of target mRNAs and miR-122 [#20, #21]. QKI further reads internal m7G-modified mRNAs and shuttles them into stress granules via G3BP1 to tune their translation [#33], and modulates AGO2/miRNA-mediated silencing as an auxiliary factor [#36]. Beyond RNA, QKI acts on chromatin as a transcriptional co-activator, binding single-stranded promoter DNA to recruit Srebp2 and the PPARβ-RXRα complex to drive cholesterol and lipid biosynthesis required for myelin [#26, #27]. These activities converge on biological programs spanning oligodendrocyte and Schwann cell myelination [#0, #6, #9], microglial myelin-debris clearance [#28], cardiac sarcomerogenesis [#29, #34], muscle stem cell asymmetric division [#32], adipose thermogenesis [#24], and post-transcriptional control of Notch, Ras-MAPK, NF-κB, and Wnt pathway components [#16, #19, #30, #41].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that QKI is expressed as isoforms with divergent subcellular localizations linked to myelinating cells, framing isoform identity as the basis of functional specialization.\",\n      \"evidence\": \"Isoform-specific antibody immunostaining in mouse nervous tissue and quaking-viable mutants\",\n      \"pmids\": [\"8987822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity of each isoform\", \"Did not identify RNA targets\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the structural logic of QKI function by mapping self-dimerization to the QUA1 domain and identifying a STAR-NLS that confers QKI-5 nucleocytoplasmic shuttling, explaining the isoforms' differential localization.\",\n      \"evidence\": \"GFP fusion localization, QUA1 mutagenesis, interspecies heterokaryon shuttling assay\",\n      \"pmids\": [\"10506177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish RNA-binding consequences of dimerization\", \"Shuttling cargo not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated that QKI is a sequence-specific translational repressor acting through 3' UTR elements, providing the first direct functional mechanism.\",\n      \"evidence\": \"In vitro binding, in vivo C. elegans reporter, genetic epistasis with tra-3\",\n      \"pmids\": [\"10535969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous mammalian targets not yet defined\", \"Repression mechanism at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified MBP mRNA as a physiological QKI target and showed QKI stabilizes and localizes it, connecting QKI molecular activity to the myelination phenotype.\",\n      \"evidence\": \"RNase protection, RNA fractionation, RNA-protein interaction, 3' UTR deletion in qkv mice\",\n      \"pmids\": [\"10864952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mRNA stabilization vs localization not separated\", \"Regulation of QKI binding not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed that QKI RNA binding is dynamically controlled by Src-PTK tyrosine phosphorylation, providing a developmental switch for myelin gene expression.\",\n      \"evidence\": \"RNA-protein interaction and phosphorylation assays with in vivo developmental time-course\",\n      \"pmids\": [\"12682013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphosites and kinases not fully resolved\", \"Generalizability to non-MBP targets unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanded the target repertoire (MAP1B) and established isoform-specific requirements for oligodendrocyte differentiation, showing RNA-binding is essential for QKI's pro-differentiation function.\",\n      \"evidence\": \"RIP, RNAi, forced expression, point mutation of RNA-binding domain, transgenic rescue, EM in qkv mice\",\n      \"pmids\": [\"16855020\", \"17079655\", \"17575274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full target set in differentiation undefined\", \"Distinct contributions of stabilization vs splicing not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the QKI binding motif as bipartite UAAY repeats and extended QKI's myelination role to Schwann cells, generalizing the recognition code across STAR proteins.\",\n      \"evidence\": \"SELEX and in vitro binding; PNS co-culture gain/loss-of-function with EM\",\n      \"pmids\": [\"19457263\", \"19517016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo motif occupancy not mapped\", \"Structural basis of bipartite recognition not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed QKI can destabilize target mRNAs (AIP-1) and physically associates with Ago2 in stress granules, broadening its repertoire to mRNA decay and RNAi machinery.\",\n      \"evidence\": \"2D-DIGE proteomics, mRNA stability assay, qkv mice; Co-IP and co-localization with Ago2\",\n      \"pmids\": [\"20631256\", \"20862255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ago2 interaction from single Co-IP without reciprocal validation\", \"Determinants of stabilize-vs-destabilize choice unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established QKI as an alternative-splicing regulator and embedded it in a cell-cycle transcriptional circuit (E2F1 feedback) and a QKI→PLP→SIRT2 myelin pathway, broadening function beyond mRNA stability.\",\n      \"evidence\": \"Splicing microarray/RT-PCR (macroH2A1), ChIP and luciferase (E2F1), genetic rescue (PLP/SIRT2)\",\n      \"pmids\": [\"21844227\", \"21768773\", \"21948283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing mechanism not yet mechanistic\", \"Direct vs indirect transcriptional effects not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Uncovered a nuclear-isoform-specific mechanism—retention of pri-miRNA with Drosha to block miRNA biogenesis—and direct 3' UTR repression of FOXO1, linking QKI to EGFR/ERK signaling and cancer.\",\n      \"evidence\": \"Nuclear fractionation, RIP, Drosha co-IP, miR-7 rescue; RIP and mRNA stability for FOXO1\",\n      \"pmids\": [\"23319046\", \"24398626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of pri-miRNA retention beyond miR-7-1 untested\", \"FOXO1 finding single-lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved a splicing mechanism in which QKI-5 competes with SF1 at the branchpoint to control NUMB and gate Notch signaling, and extended 3' UTR control to SOX2 and cardiac FoxO1.\",\n      \"evidence\": \"Splicing reporter and SF1 competition binding (NUMB); RIP/QRE mapping (SOX2); in vivo I/R model (FoxO1)\",\n      \"pmids\": [\"24722255\", \"24918581\", \"25068621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SF1 competition across targets not established\", \"SOX2 and FoxO1 findings single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined QKI-7 as the cytoplasmic-polyadenylation isoform via PAPD4/GLD-2 recruitment and mapped transcriptome-wide binding by iCLIP, linking binding position to splicing direction and to Ras-MAPK control via RASA1.\",\n      \"evidence\": \"Co-IP, poly(A) and tethered reporter assays (QKI-7/PAPD4); iCLIP-seq (ADD3); RIP/stability (RASA1)\",\n      \"pmids\": [\"26926106\", \"33196842\", \"27767378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing position-dependent splicing incompletely defined\", \"RASA1 finding single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established QKI as a chromatin-acting transcriptional co-activator of PPARβ-RXRα and broadened isoform-specific roles to vascular, endothelial, adipose, and lipid-uptake programs.\",\n      \"evidence\": \"Oligodendrocyte conditional KO with lipidomics and agonist rescue (PPARβ); RIP/splicing (HDAC7), mRNA decay (CD144/NLGN1/TSG-6), conditional KO (UCP1/PGC1α); luciferase (SRA); GLD-2/Ago2 adenylation of miR-122\",\n      \"pmids\": [\"32202512\", \"31331967\", \"32732889\", \"31868295\", \"26056009\", \"31792053\", \"28186995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of QKI recruitment to nuclear receptor complexes incompletely defined\", \"Several tissue findings single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cemented QKI's dual nucleic-acid roles—single-stranded DNA-binding co-activation of Srebp2 cholesterol biosynthesis and broad splicing/RNA-stability control of cardiac, microglial, muscle, immune, and Wnt programs.\",\n      \"evidence\": \"ChIP and Co-IP (Srebp2/Pol II) with conditional KO and sterol rescue; conditional KOs and CRISPR in microglia, cardiomyocytes, muscle stem cells, macrophages, and BMSCs with transcriptomic/functional readouts\",\n      \"pmids\": [\"34021134\", \"33942715\", \"33045062\", \"33397958\", \"32382069\", \"33758177\", \"37460362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How QKI selects DNA vs RNA targets unresolved\", \"Several lineage phenotypes from single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified QKI as a reader of internal m7G-modified mRNAs that, via G3BP1, routes transcripts into stress granules and reshapes translation, and defined an auxiliary role in AGO2/let-7b silencing.\",\n      \"evidence\": \"Transcriptome-wide m7G profiling, G3BP1 Co-IP, stress granule imaging, translation assay; PAR-CLIP, AGO-depleted cells, single-molecule imaging\",\n      \"pmids\": [\"37379838\", \"38372062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of m7G recognition not resolved\", \"Interplay between m7G reading and QRE binding unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed QKI controls alternative polyadenylation site choice to regulate lncRNA isoform balance (NEAT1) and paraspeckle-driven glioma migration, adding 3'-end processing to its mechanistic repertoire.\",\n      \"evidence\": \"CRISPR-Cas9 PAS deletion, RNA-binding and isoform quantification, migration assay\",\n      \"pmids\": [\"39032650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of QKI-directed APA across transcriptome untested\", \"Mechanism linking QKI binding to PAS selection unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How QKI integrates its many partial mechanisms—choosing among stabilization, destabilization, splicing, polyadenylation, m7G reading, and DNA-binding co-activation at a given target—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model for target-by-target outcome selection\", \"No structural determinant distinguishing DNA vs RNA engagement\", \"Crosstalk between phosphorylation, isoform identity, and partner availability not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 5, 8, 10, 15, 16, 18, 20, 24, 33, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [26, 27, 39]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 20, 33]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 5, 15, 16, 18, 20, 33, 35]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [26, 27, 39]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 26, 27, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 19, 30, 41]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 29, 32, 34]}\n    ],\n    \"complexes\": [\"stress granule\"],\n    \"partners\": [\"PAPD4\", \"G3BP1\", \"AGO2\", \"DROSHA\", \"SF1\", \"SREBF2\", \"PPARD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}