{"gene":"LIN28A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2011,"finding":"LIN28A recruits the TUTase Zcchc11/TUT4 to precursor let-7 in the cytoplasm, inducing polyuridylation that blocks Dicer processing. This mechanism is distinct from LIN28B, which acts in the nucleus by sequestering primary let-7 transcripts and inhibiting Microprocessor processing in a Zcchc11-independent manner.","method":"Zcchc11 depletion, subcellular fractionation, functional assays in cancer cell lines and xenografts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, localization, functional rescue), replicated across multiple cell lines and in vivo xenografts, mechanistically distinguishes LIN28A vs LIN28B pathways","pmids":["22118463"],"is_preprint":false},{"year":2009,"finding":"C. elegans LIN-28 directly binds precursor let-7 miRNA to prevent Dicer processing, and stimulates uridylation of pre-let-7 by the poly(U) polymerase PUP-2 in vitro. LIN-28 and PUP-2 interact directly, establishing the conserved uridylation-based mechanism for let-7 suppression.","method":"In vitro uridylation assay, direct binding assays, C. elegans genetics, in vivo functional experiments","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of uridylation, direct protein-RNA and protein-protein interaction assays, genetic validation in vivo","pmids":["19713957"],"is_preprint":false},{"year":2007,"finding":"Lin-28 binds IGF-2 mRNA and associates with polysomes and translation initiation complexes in skeletal myoblasts, increasing translational efficiency of IGF-2. Lin-28 was also found in stress granules (stalled mRNA-protein translation complexes), supporting its role as a translational enhancer.","method":"RNA immunoprecipitation, polysome fractionation, loss-of-function and gain-of-function assays in cultured myoblasts, biochemical co-fractionation, stress granule localization","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated by biochemical pulldown, polysome association, functional rescue assays, multiple orthogonal methods in single study","pmids":["17473174"],"is_preprint":false},{"year":2013,"finding":"LIN28A represses miR-9 precursor processing through a uridylation-independent mechanism during neuronal differentiation, reducing mature miR-9 levels and thereby controlling differentiation capacity of P19 cells.","method":"P19 cell differentiation assay, inducible LIN28A expression system, miRNA processing assays, loss-of-function experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible and constitutive expression systems with multiple readouts, single lab, two orthogonal methods","pmids":["24722317"],"is_preprint":false},{"year":2014,"finding":"The E3 ligase Trim25 binds the conserved terminal loop of pre-let-7 and acts as an RNA-specific cofactor that activates TUT4, enabling more efficient Lin28A-mediated uridylation of pre-let-7. This cofactor specificity explains why, despite Lin28A binding many pre-miRNAs, only pre-let-7 is efficiently uridylated.","method":"RNA pulldown coupled with quantitative mass spectrometry, RNA binding assays, TuT4 activity assays, identification of Trim25 as cofactor","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — RNA pulldown with quantitative MS to identify cofactor, functional validation of uridylation enhancement, mechanistic in vitro assays in single rigorous study","pmids":["25457611"],"is_preprint":false},{"year":2018,"finding":"LIN28 CSD recognizes a (U)GAU motif on pre-let-7, partitioning let-7 family members into CSD+ and CSD- subclasses. CSD+ precursors undergo more efficient in vivo recognition, 3′ uridylation, and degradation, resulting in stronger suppression in LIN28-activated cells.","method":"Single-nucleotide-resolution in vivo CLIP mapping of LIN28 binding sites, analysis of uridylation and degradation of let-7 subclasses","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — single-nucleotide resolution CLIP-seq with functional validation of differential suppression, rigorous mechanistic dissection of CSD binding motif","pmids":["30029005"],"is_preprint":false},{"year":2014,"finding":"PCAF directly interacts with and acetylates Lin28 at the cold shock domain (CSD), leading to reduced Lin28 protein levels and increased mature let-7a. SIRT1 reverses this acetylation. The PCAF/SIRT1 balance regulates Lin28 activity in let-7a biogenesis.","method":"Co-immunoprecipitation, in vitro acetylation assay, domain mapping, SIRT1 deacetylation assay, let-7a level measurement","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro acetylation assay, co-IP for interaction, domain mapping to CSD, functional consequence on let-7a levels; multiple orthogonal methods in single study","pmids":["24631505"],"is_preprint":false},{"year":2014,"finding":"ERK1/2 kinases directly phosphorylate Lin28a at Ser-200. Phospho-mimetic (S200D) Lin28a shows impaired inhibition of let-7 miRNA and decreased cyclin D1; phospho-deficient (S200A) Lin28a expresses less let-7, proliferates faster, and exhibits a differentiation defect. ERK-mediated phosphorylation thus modulates Lin28a's ability to suppress let-7 and regulate pluripotency.","method":"In vitro kinase assay, CRISPR/Cas9 knock-in of S200A and S200D mutants in P19 cells, let-7 miRNA measurement, proliferation and differentiation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus CRISPR knock-in of phospho-mutants with functional readouts, multiple orthogonal methods in one study","pmids":["28179426"],"is_preprint":false},{"year":2018,"finding":"USP28, a deubiquitinating enzyme, interacts with LIN28A and reverses its proteasomal ubiquitination-dependent degradation, thereby stabilizing LIN28A protein and extending its half-life. USP28-mediated stabilization of LIN28A enhances cancer cell viability and migration.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, cancer cell functional assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for interaction, ubiquitination assay, functional consequence on protein stability and cell phenotype; single lab, two orthogonal methods","pmids":["30543854"],"is_preprint":false},{"year":2020,"finding":"LIN28A is SUMOylated in vivo and in vitro at Lys-15, a modification that increases its binding affinity for pre-let-7, enhances TUT4 recruitment, and blocks DICER processing, thereby amplifying suppression of mature let-7. SUMOylation is increased by hypoxia and reduced by chemotherapy drugs (Cisplatin, Paclitaxel). A K15R SUMOylation-deficient mutant abolishes these effects.","method":"In vivo and in vitro SUMOylation assays, mutagenesis (K15R), pre-let-7 binding affinity assay, TUT4 recruitment assay, DICER processing assay, in vivo tumor growth assay","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro and in vivo SUMOylation with site mutagenesis, direct binding affinity measurement, mechanistic dissection of TUT4 recruitment and DICER blockade; multiple orthogonal methods in single study","pmids":["32333719"],"is_preprint":false},{"year":2019,"finding":"Lin28a directly binds Pck2 mRNA (mitochondrial phosphoenolpyruvate carboxykinase 2) and increases its transcript level. Cardiac-specific deletion of Lin28a attenuates pressure overload-induced hypertrophy; increasing Pck2 is sufficient to promote hypertrophic growth similar to Lin28a overexpression; epistatic analysis shows Pck2 mediates Lin28a's role in cardiac hypertrophic growth and glycolytic reprogramming.","method":"RNA immunoprecipitation, cardiac-specific Lin28a knockout, transverse aortic constriction model, epistasis analysis, metabolomic analysis, Pck2 knockdown/overexpression","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-IP for direct mRNA binding, cardiac-specific KO with defined phenotype, epistasis with Pck2, metabolomics; multiple orthogonal methods, in vivo and in vitro","pmids":["30636447"],"is_preprint":false},{"year":2021,"finding":"LIN28 binds small nucleolar RNAs (snoRNAs) and rRNA to maintain nucleolar integrity. LIN28 resides in a complex with Nucleolin (NCL) and the transcriptional repressor TRIM28 at the Dux and rDNA loci. Loss of LIN28 causes nucleolar phase separation defects, ribosomal stress, P53 activation, and de-repression of the 2C transcription factor Dux.","method":"Chromatin immunoprecipitation, RNA binding assays for snoRNAs/rRNA, co-immunoprecipitation of NCL/TRIM28 complex, LIN28 knockout in pluripotent stem cells, nucleolar imaging","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for complex, ChIP for locus occupancy, KO with defined nucleolar and transcriptional phenotype; single lab with multiple orthogonal methods","pmids":["34331666"],"is_preprint":false},{"year":2021,"finding":"Lin28a directly binds the mRNA of Lars2 (mitochondrial leucyl-tRNA synthetase) and suppresses its translation. Overexpression of LARS2 reversed Lin28a-induced estrogen downregulation and mitochondrial dysfunction in human granulosa cells.","method":"RNA immunoprecipitation for direct mRNA binding, LARS2 overexpression rescue, measurement of estrogen, ATP, mitochondrial membrane potential in LIN28A overexpression/knockdown cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP confirming direct binding, rescue experiment establishing epistasis; single lab, two orthogonal methods","pmids":["36436798"],"is_preprint":false},{"year":2021,"finding":"LIN28A directly binds the GGAGA motif in the promoter region of CENPE mRNA (as shown by RIP, RNA pulldown, and dual luciferase reporter assays), promoting CENPE expression and thereby sustaining proliferation and chemoresistance in AML cells.","method":"RNA immunoprecipitation (RIP), RNA pulldown, dual luciferase reporter assay, CENPE knockdown rescue, AML cell proliferation and apoptosis assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + RNA pulldown + luciferase reporter, functional rescue by CENPE KD; single lab, multiple orthogonal methods","pmids":["34868981"],"is_preprint":false},{"year":2022,"finding":"LIN28A recruits RNA-binding protein MSI2 via its CSD domain (interacting with MSI2's RRM domain) to directly induce mRNA decay of YAP1 upstream kinases (MST1/2 and LATS1/2), inhibiting the Hippo pathway and activating YAP1 to promote cancer stem cell properties, independently of let-7.","method":"Co-immunoprecipitation, domain mapping (CSD of LIN28 and RRM of MSI2), transcriptome analysis, LIN28A/MSI2 knockdown with YAP1 constitutive activation rescue, mRNA stability assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, transcriptome analysis, in vivo xenograft rescue; single lab, multiple orthogonal methods","pmids":["35102250"],"is_preprint":false},{"year":2014,"finding":"Lin28 loss-of-function in C. elegans uses two distinct steps: first, a let-7-independent positive regulation of hbl-1 through its 3′ UTR to control L2 stage cell fates; second, a let-7-dependent step controlling subsequent fates via repression of lin-41. This two-step mechanism is separable by genetics.","method":"C. elegans genetic epistasis, let-7 pathway double mutants, lin-28/let-7/lin-41 genetic interaction analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis in multiple double-mutant combinations demonstrating two separable mechanistic activities, replicated across multiple alleles","pmids":["22457637"],"is_preprint":false},{"year":2022,"finding":"RNA-IP sequencing in cardiomyocytes identified long noncoding RNA H19 as the most significantly altered LIN28a target after injury. Ablation of H19 blunted LIN28a-induced enhancement of cardiomyocyte metabolism and cell cycle activity, placing H19 downstream of LIN28a in cardiac repair.","method":"RNA immunoprecipitation sequencing (RIP-seq) from LIN28a-overexpressing cardiomyocytes after injury, H19 ablation rescue assay, cell cycle and metabolism assays","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq for direct target identification, functional epistasis via H19 ablation; single lab, two orthogonal methods","pmids":["36314132"],"is_preprint":false},{"year":2016,"finding":"Lin28a overexpression in Drosophila intestinal stem cells boosts insulin signaling by increasing translation of Insulin-like Receptor (InR) mRNA, promoting symmetric division and stem cell expansion. Forced expression of InR completely rescues lin-28 null mutant defects in stem cell number and division pattern. This stem cell activity is independent of let-7.","method":"Drosophila lin-28 null mutant analysis, immunoprecipitation of Lin-28-bound mRNAs, InR forced expression rescue, lin-28/let-7 epistasis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA immunoprecipitation identifying InR as target, genetic rescue demonstrating epistasis, let-7 independence confirmed; single lab, multiple methods","pmids":["26487778"],"is_preprint":false},{"year":2014,"finding":"LIN28A expression in sickle cell erythrocytes increases fetal hemoglobin (HbF), reduces beta(sickle)-globin expression, and strongly suppresses all members of the let-7 miRNA family, reducing sickling morphology without impairing differentiation or enucleation.","method":"Lentiviral LIN28A transgenic expression in CD34+ sickle cells, measurement of HbF, beta-globin, let-7 levels, erythrocyte morphology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct LIN28A overexpression with let-7 measurement and phenotypic rescue; single lab, mechanistically links LIN28A to let-7 suppression and globin switching","pmids":["25188417"],"is_preprint":false},{"year":2021,"finding":"Lin28a-containing high-molecular-weight complexes in mouse ESCs include helicases Ddx3x and other RNA-binding proteins (Hnrnph1, Hnrnpu, Syncrip). Suppression of Ddx3x, Hnrnph1, Hnrnpu, or Syncrip interferes with Lin28a binding to Dnmt3a mRNA, demonstrating that these proteins form an oligomeric RNP complex required for Lin28a-mediated translational regulation of Dnmt3a, independently of let-7.","method":"Purification of Lin28a-containing complexes, proteomic identification of interactors, RNAi-mediated knockdown of candidates, RNA immunoprecipitation of Lin28a-Dnmt3a mRNA interaction","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex purification with proteomics, RNAi epistasis confirming each partner's requirement for mRNA binding; single lab, multiple orthogonal methods","pmids":["33504840"],"is_preprint":false},{"year":2016,"finding":"Lin28 proteins directly bind a conserved element in the 3′ UTR of Hmga2 mRNA, causing down-regulation of its translation in differentiating ESCs, independently of let-7. This let-7-independent mechanism prevents inappropriate accumulation of Hmga2 and aberrant proliferation/apoptosis.","method":"RNA immunoprecipitation for Lin28-Hmga2 3′UTR binding, let-7-independent translational regulation assay, Hmga2 protein measurement in Lin28 knockdown/overexpression cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP demonstrating direct binding plus functional consequence on Hmga2 protein levels; single lab, two methods","pmids":["27920151"],"is_preprint":false},{"year":2021,"finding":"LIN28 binding is ~99% to non-miRNA transcripts (protein-coding and ribosomal RNAs), and these non-miRNA binding sites are specific and strong but do not mediate direct post-transcriptional regulation. Instead, they sequester LIN28 protein, reducing its functional availability to regulate let-7 miRNA biogenesis.","method":"Transcriptome-wide CLIP-seq mapping of LIN28 binding sites, quantification of miRNA vs. non-miRNA binding proportions, functional assessment of let-7 regulation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide single-nucleotide CLIP mapping, quantitative analysis of binding proportions and functional consequence; single lab, rigorous single study","pmids":["34380031"],"is_preprint":false},{"year":2009,"finding":"RKIP suppresses LIN28 transcription via inhibition of MAPK signaling, which leads to decreased Myc-driven LIN28 transcription. Suppression of LIN28 enables let-7 processing, which in turn inhibits HMGA2. LIN28 depletion and let-7 expression suppress bone metastasis; LIN28 re-expression restores bone metastasis in RKIP-expressing cells.","method":"Epistasis via LIN28 depletion/rescue in breast cancer cells and orthotopic murine model, MAPK inhibition, let-7 measurement, HMGA2 quantification","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo epistasis with LIN28 depletion and rescue in murine model, pathway validation; single lab, multiple orthogonal methods","pmids":["19153603"],"is_preprint":false},{"year":2016,"finding":"The small molecule N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide blocks LIN28/let-7 interaction (confirmed by FRET assay), rescues let-7 processing and function in Lin28-expressing cancer cells, and a biotinylated derivative captures Lin28 from cell lysates, confirming on-target engagement.","method":"Protein/RNA FRET assay screening, biotinylated derivative pulldown from cell lysates, let-7 processing assay in cancer cells, tumor sphere formation assay, ESC differentiation assay","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical FRET inhibition, pulldown from cells confirming target engagement, functional rescue of let-7; single lab, multiple orthogonal methods","pmids":["27548809"],"is_preprint":false},{"year":2019,"finding":"LIN28A loss-of-function variant (R192G) causes developmental defects and Parkinson's disease-related phenotypes in midbrain dopamine neurons derived from patient iPSCs. Conditional Lin28 knockout in mice leads to midbrain dopamine neuron degeneration and PD-related behavioral deficits. Wild-type Lin28A expression rescues R192G phenotypes.","method":"Lin28 conditional knockout mice, isogenic hESC/hiPSC-based disease model with R192G variant, neuronal differentiation assays, cell transplantation in PD model rats with behavioral testing","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in mice, isogenic patient iPSC model with rescue by WT LIN28A, transplantation in rat PD model; multiple orthogonal in vivo methods","pmids":["31750563"],"is_preprint":false},{"year":2014,"finding":"LIN28A knockdown in human trophoblast cells (ACH-3P) results in increased spontaneous syncytialization and upregulation of syncytiotrophoblast markers (hCG, LGALS13, ERVW-1), demonstrating that LIN28A has a functional role in restricting trophoblast differentiation in human but not mouse trophoblast stem cells.","method":"shRNA-mediated LIN28A knockdown, mRNA degradation targeting, syncytialization assay, syncytiotrophoblast marker quantification in ACH-3P and mTS cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific KD with defined differentiation phenotype and marker upregulation; single lab, two methods (shRNA + targeted mRNA degradation)","pmids":["24006280"],"is_preprint":false},{"year":2014,"finding":"LIN28A binds the promoter region GGAGA motif of CENPE and also stabilizes mRNAs such as ATG12 (as shown for LIN28A in the context of DDX11-AS1-mediated chemoresistance). LIN28A stabilizes ATG7 and ATG12 mRNA by increasing their mRNA stability.","method":"RNA immunoprecipitation, mRNA stability assay, Western blot for ATG7/ATG12","journal":"Pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay and mRNA stability assay, single lab; limited mechanistic detail on direct binding vs indirect stabilization","pmids":["36382664"],"is_preprint":false},{"year":2016,"finding":"MeCP2 binds to methylated CpG islands at the LIN28A promoter and suppresses LIN28A transcription. MeCP2 knockdown transcriptionally activates LIN28A expression. LIN28A expression level is directly associated with CpG methylation status of two promoter-region CpG islands.","method":"Bisulfite sequencing, ChIP assay for MeCP2 at LIN28A promoter, MeCP2 knockdown, 5-Aza-CdR treatment, LIN28A mRNA/protein measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct MeCP2 binding, bisulfite sequencing of methylation state, functional knockdown; single lab, multiple orthogonal methods","pmids":["26910839"],"is_preprint":false}],"current_model":"LIN28A is a bipartite RNA-binding protein (cold shock domain + zinc knuckle domain) that acts primarily in the cytoplasm to block let-7 miRNA biogenesis by binding pre-let-7 and recruiting the TUTase TUT4/Zcchc11 (facilitated by the cofactor Trim25) to polyuridylate the precursor, targeting it for degradation; its CSD recognizes a (U)GAU motif partitioning let-7 precursors into high- and low-efficiency suppression subclasses, while ~99% of its binding occurs on non-miRNA transcripts that sequester its activity; post-translationally, LIN28A is acetylated by PCAF (reversed by SIRT1), phosphorylated by ERK1/2 at Ser-200 to impair let-7 suppression, SUMOylated at Lys-15 to enhance let-7 suppression and TUT4 recruitment, ubiquitinated for proteasomal degradation (reversed by USP28), and also acts in let-7-independent modes by directly binding and regulating translation or stability of specific mRNAs including IGF-2, Pck2, Hmga2, Dnmt3a, Lars2, and H19, in some cases within oligomeric RNP complexes; in the nucleus, LIN28A associates with snoRNAs/rRNA and a Nucleolin/TRIM28 complex to maintain nucleolar integrity and repress the 2C transcriptional program."},"narrative":{"mechanistic_narrative":"LIN28A is a bipartite RNA-binding protein that governs cell fate, proliferation, and metabolic programs primarily by blocking biogenesis of the let-7 family of microRNAs [PMID:22118463, PMID:19713957]. In the cytoplasm it binds precursor let-7 and recruits the terminal uridylyltransferase TUT4/Zcchc11 to polyuridylate the precursor and block Dicer processing — a conserved mechanism reconstituted from C. elegans LIN-28/PUP-2 to human cells, and mechanistically distinct from the nuclear, uridylation-independent route used by LIN28B [PMID:22118463, PMID:19713957]. Selectivity for let-7 among many bound pre-miRNAs is conferred at two levels: the E3 ligase Trim25 binds the pre-let-7 terminal loop to activate TUT4 [PMID:25457611], and the cold-shock domain recognizes a (U)GAU motif that partitions let-7 members into efficiently versus poorly suppressed subclasses [PMID:30029005]; meanwhile the large majority of LIN28A binding occurs on non-miRNA transcripts that sequester the protein away from let-7 regulation [PMID:34380031]. This let-7 axis is tuned by an extensive set of post-translational modifications: PCAF acetylates the CSD to destabilize LIN28A and is reversed by SIRT1 [PMID:24631505], ERK1/2 phosphorylates Ser-200 to impair let-7 suppression [PMID:28179426], SUMOylation at Lys-15 enhances pre-let-7 binding and TUT4 recruitment [PMID:32333719], and USP28-mediated deubiquitination stabilizes the protein against proteasomal turnover [PMID:30543854]. LIN28A also acts independently of let-7 by directly binding specific transcripts to control their translation or stability — enhancing IGF-2 [PMID:17473174] and InR [PMID:26487778] translation, repressing Hmga2 [PMID:27920151] and Lars2 [PMID:36436798], regulating Dnmt3a within an oligomeric RNP containing Ddx3x, Hnrnph1, Hnrnpu and Syncrip [PMID:33504840], inducing decay of Hippo-pathway kinase mRNAs via MSI2 to activate YAP1 [PMID:35102250], and acting through Pck2 and the lncRNA H19 in cardiac growth and repair [PMID:30636447, PMID:36314132]. In the nucleus it associates with snoRNAs/rRNA and a Nucleolin/TRIM28 complex to maintain nucleolar integrity and repress the 2C/Dux program [PMID:34331666]. A loss-of-function R192G variant causes midbrain dopamine neuron degeneration and Parkinson's-related phenotypes, rescued by wild-type LIN28A [PMID:31750563].","teleology":[{"year":2007,"claim":"Established the first molecular activity of Lin-28 — direct binding of a target mRNA to enhance its translation — defining it as a positive translational regulator before the let-7 connection was known.","evidence":"RNA-IP, polysome fractionation, and gain/loss-of-function in myoblasts showing IGF-2 binding and stress-granule localization","pmids":["17473174"],"confidence":"High","gaps":["Did not address let-7 or miRNA biogenesis","Mechanism of translational enhancement not resolved at nucleotide level"]},{"year":2009,"claim":"Defined the conserved core mechanism of let-7 suppression by showing LIN-28 binds pre-let-7 and directly stimulates its uridylation by a poly(U) polymerase.","evidence":"In vitro uridylation reconstitution, direct binding assays, and C. elegans genetics with PUP-2","pmids":["19713957"],"confidence":"High","gaps":["Human TUTase identity not established here","Cofactor requirements for specificity unknown"]},{"year":2009,"claim":"Placed LIN28 within an oncogenic signaling circuit by showing it is a MAPK/Myc-driven transcriptional output whose suppression unleashes let-7 to block metastasis.","evidence":"LIN28 depletion/rescue epistasis in breast cancer cells and orthotopic murine model with let-7 and HMGA2 readouts","pmids":["19153603"],"confidence":"Medium","gaps":["Indirect transcriptional regulation, not direct LIN28 activity","Did not dissect which let-7 targets drive metastasis"]},{"year":2011,"claim":"Resolved the human mechanism and distinguished LIN28A from LIN28B, showing LIN28A recruits TUT4/Zcchc11 to cytoplasmic pre-let-7 whereas LIN28B acts nuclearly and TUTase-independently.","evidence":"Zcchc11 depletion, subcellular fractionation, and functional rescue across cancer cell lines and xenografts","pmids":["22118463"],"confidence":"High","gaps":["Did not explain how only let-7 is selected among bound pre-miRNAs","Regulation of TUT4 recruitment unaddressed"]},{"year":2014,"claim":"Separated LIN28's let-7-dependent and let-7-independent activities genetically, showing it controls successive developmental cell fates through two distinct mechanisms.","evidence":"C. elegans epistasis with let-7/lin-41 and hbl-1 3'UTR regulation across multiple alleles","pmids":["22457637"],"confidence":"High","gaps":["Molecular mechanism of hbl-1 3'UTR regulation not defined","Mammalian equivalence of two-step model not shown"]},{"year":2014,"claim":"Explained let-7 selectivity by identifying Trim25 as an RNA-specific cofactor that activates TUT4 on the pre-let-7 terminal loop.","evidence":"RNA pulldown with quantitative mass spectrometry and in vitro TUT4 activity assays","pmids":["25457611"],"confidence":"High","gaps":["Structural basis of Trim25 loop recognition unresolved","Whether Trim25 acts on let-7-independent targets unknown"]},{"year":2014,"claim":"Opened the post-translational regulation of LIN28A by showing acetylation (PCAF) and phosphorylation (ERK1/2 at Ser-200) modulate its stability and let-7-suppressing activity.","evidence":"In vitro acetylation/kinase assays, domain mapping, SIRT1 reversal, and CRISPR phospho-mutant knock-ins with functional readouts","pmids":["24631505","28179426"],"confidence":"High","gaps":["Upstream signals integrating these modifications in vivo not mapped","Crosstalk between modifications not addressed"]},{"year":2016,"claim":"Extended the let-7-independent translational mechanism to mammalian stem-cell programs, showing direct binding of Hmga2 and InR transcripts controls differentiation and stem-cell expansion.","evidence":"RNA-IP and genetic rescue in differentiating ESCs (Hmga2) and Drosophila intestinal stem cells (InR)","pmids":["27920151","26487778"],"confidence":"Medium","gaps":["Binding-site determinants of let-7-independent targets not generalized","How target choice is partitioned from let-7 activity unclear"]},{"year":2016,"claim":"Demonstrated druggability and validated the LIN28/let-7 interaction as the on-target node using a small-molecule inhibitor.","evidence":"FRET-based inhibition screen, biotinylated-probe pulldown, and let-7 rescue in cancer cells","pmids":["27548809"],"confidence":"Medium","gaps":["Selectivity over let-7-independent functions not tested","In vivo efficacy not established"]},{"year":2018,"claim":"Defined the sequence logic of CSD recognition, showing a (U)GAU motif sorts let-7 precursors into high- and low-efficiency suppression subclasses.","evidence":"Single-nucleotide-resolution in vivo CLIP with uridylation and degradation analysis of let-7 subclasses","pmids":["30029005"],"confidence":"High","gaps":["Functional consequence of subclass partitioning across tissues unmapped","Interplay with Trim25 loop recognition not integrated"]},{"year":2018,"claim":"Identified deubiquitination as a stability control point, with USP28 reversing proteasomal turnover to extend LIN28A half-life and promote cancer phenotypes.","evidence":"Co-IP, ubiquitination and protein half-life assays, and cancer cell functional readouts","pmids":["30543854"],"confidence":"Medium","gaps":["E3 ligase driving ubiquitination not identified","Single-lab two-method evidence for the interaction"]},{"year":2019,"claim":"Linked LIN28A to a Mendelian-relevant neurodegenerative phenotype, showing an R192G loss-of-function variant drives midbrain dopamine neuron degeneration rescuable by wild-type protein.","evidence":"Conditional KO mice, isogenic patient iPSC model with WT rescue, and transplantation in a rat PD model","pmids":["31750563"],"confidence":"High","gaps":["Molecular target whose dysregulation by R192G causes degeneration not defined","Whether let-7 or let-7-independent activity mediates the phenotype unresolved"]},{"year":2019,"claim":"Established a let-7-independent metabolic role, showing direct Pck2 mRNA binding mediates cardiac hypertrophic growth and glycolytic reprogramming.","evidence":"RNA-IP, cardiac-specific KO, transverse aortic constriction, epistasis, and metabolomics","pmids":["30636447"],"confidence":"High","gaps":["How LIN28A increases Pck2 transcript level mechanistically unclear","Generalizability beyond cardiac tissue untested"]},{"year":2020,"claim":"Added SUMOylation at Lys-15 as an activating modification that boosts pre-let-7 binding and TUT4 recruitment, linking stress signals to let-7 suppression.","evidence":"In vivo/in vitro SUMOylation assays, K15R mutagenesis, binding affinity and DICER processing assays, and tumor growth model","pmids":["32333719"],"confidence":"High","gaps":["SUMO E3 ligase and protease enzymes not identified","Crosstalk with phosphorylation/acetylation marks unmapped"]},{"year":2021,"claim":"Revealed a nuclear/nucleolar function distinct from let-7, showing LIN28 binds snoRNAs/rRNA and resides in an NCL/TRIM28 complex maintaining nucleolar integrity and repressing the 2C/Dux program.","evidence":"ChIP, snoRNA/rRNA binding assays, NCL/TRIM28 co-IP, and KO with nucleolar imaging in pluripotent stem cells","pmids":["34331666"],"confidence":"Medium","gaps":["Direct vs indirect role in phase separation unresolved","Single-lab evidence for the NCL/TRIM28 complex"]},{"year":2021,"claim":"Reframed binding stoichiometry by showing ~99% of LIN28 binding is to non-miRNA transcripts that sequester the protein rather than being directly regulated.","evidence":"Transcriptome-wide single-nucleotide CLIP with quantification of miRNA vs non-miRNA binding and let-7 functional assessment","pmids":["34380031"],"confidence":"Medium","gaps":["Whether sequestration is dynamically regulated unknown","Reconciliation with documented functional mRNA targets not fully addressed"]},{"year":2021,"claim":"Defined LIN28A as a subunit of oligomeric RNP complexes required for let-7-independent mRNA regulation, with multiple RNA-binding partners needed for target engagement.","evidence":"Complex purification, proteomics, and RNAi epistasis showing Ddx3x/Hnrnph1/Hnrnpu/Syncrip are required for Lin28a binding to Dnmt3a mRNA","pmids":["33504840"],"confidence":"Medium","gaps":["Architecture and stoichiometry of the RNP not resolved","Whether the same complex serves other targets unknown"]},{"year":2022,"claim":"Identified a let-7-independent oncogenic mechanism in which LIN28A recruits MSI2 to degrade Hippo-pathway kinase mRNAs, activating YAP1 and cancer stem-cell properties.","evidence":"Co-IP with CSD/RRM domain mapping, transcriptome analysis, mRNA stability assays, and YAP1 rescue in xenografts","pmids":["35102250"],"confidence":"Medium","gaps":["Direct binding to kinase mRNAs vs MSI2-bridged binding not fully separated","Single-lab evidence"]},{"year":2022,"claim":"Extended let-7-independent control to noncoding RNA and additional metabolic targets, placing H19 and Lars2 downstream of LIN28A in cardiac repair and ovarian mitochondrial function.","evidence":"RIP-seq/RNA-IP for direct binding and ablation/overexpression rescue (H19 in cardiomyocytes; Lars2 in granulosa cells)","pmids":["36314132","36436798"],"confidence":"Medium","gaps":["Binding-site features distinguishing these targets not defined","Single-lab two-method evidence each"]},{"year":null,"claim":"How LIN28A integrates its parallel modifications and partitions activity between let-7 suppression, sequestration on abundant non-miRNA RNAs, and diverse let-7-independent mRNA/ncRNA targets within a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to target choice","Structural basis of simultaneous CSD/zinc-knuckle target recognition across target classes lacking","Which activity drives the R192G neurodegeneration phenotype unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,5,10,12,16,19,20,21]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,17,19,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,4,5,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,17,19,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,17,18,24,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,22,24]}],"complexes":["LIN28A-TUT4/Zcchc11-Trim25 uridylation complex","Lin28a-Ddx3x/Hnrnph1/Hnrnpu/Syncrip RNP","LIN28-Nucleolin-TRIM28 nucleolar complex"],"partners":["TUT4","TRIM25","PCAF","SIRT1","USP28","MSI2","NCL","DDX3X"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H9Z2","full_name":"Protein lin-28 homolog A","aliases":["Zinc finger CCHC domain-containing protein 1"],"length_aa":209,"mass_kda":22.7,"function":"RNA-binding protein that inhibits processing of pre-let-7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism (PubMed:21247876). Seems to recognize a common structural G-quartet (G4) feature in its miRNA and mRNA targets (Probable). 'Translational enhancer' that drives specific mRNAs to polysomes and increases the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in mRNA stabilization. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression. Suppressor of microRNA (miRNA) biogenesis, including that of let-7, miR107, miR-143 and miR-200c. Specifically binds the miRNA precursors (pre-miRNAs), recognizing an 5'-GGAG-3' motif found in pre-miRNA terminal loop, and recruits TUT4 and TUT7 uridylyltransferases (PubMed:18951094, PubMed:19703396, PubMed:22118463, PubMed:22898984). This results in the terminal uridylation of target pre-miRNAs (PubMed:18951094, PubMed:19703396, PubMed:22118463, PubMed:22898984). Uridylated pre-miRNAs fail to be processed by Dicer and undergo degradation. The repression of let-7 expression is required for normal development and contributes to maintain the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells (PubMed:18951094, PubMed:19703396, PubMed:22118463, PubMed:22898984). Localized to the periendoplasmic reticulum area, binds to a large number of spliced mRNAs and inhibits the translation of mRNAs destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Binds to and enhances the translation of mRNAs for several metabolic enzymes, such as PFKP, PDHA1 or SDHA, increasing glycolysis and oxidative phosphorylation. Which, with the let-7 repression may enhance tissue repair in adult tissue (By similarity)","subcellular_location":"Cytoplasm; Rough endoplasmic reticulum; Cytoplasm, P-body; Cytoplasm, Stress granule; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9H9Z2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIN28A","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LIN28A","total_profiled":1310},"omim":[{"mim_id":"620424","title":"ZYGOTE ARREST 1-LIKE; ZAR1L","url":"https://www.omim.org/entry/620424"},{"mim_id":"618703","title":"ZINC FINGER PROTEIN 281; ZNF281","url":"https://www.omim.org/entry/618703"},{"mim_id":"613692","title":"TERMINAL URIDYLYL TRANSFERASE 4; TUT4","url":"https://www.omim.org/entry/613692"},{"mim_id":"613467","title":"ZINC FINGER CCHC DOMAIN-CONTAINING PROTEIN 6; ZCCHC6","url":"https://www.omim.org/entry/613467"},{"mim_id":"611043","title":"LIN28 HOMOLOG A; LIN28A","url":"https://www.omim.org/entry/611043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Rods & Rings","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":4.9}],"url":"https://www.proteinatlas.org/search/LIN28A"},"hgnc":{"alias_symbol":["LIN-28","FLJ12457","ZCCHC1","CSDD1"],"prev_symbol":["LIN28"]},"alphafold":{"accession":"Q9H9Z2","domains":[{"cath_id":"2.40.50.140","chopping":"39-122_135-177","consensus_level":"medium","plddt":91.9199,"start":39,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9Z2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9Z2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9Z2-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIN28A","jax_strain_url":"https://www.jax.org/strain/search?query=LIN28A"},"sequence":{"accession":"Q9H9Z2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H9Z2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H9Z2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9Z2"}},"corpus_meta":[{"pmid":"22118463","id":"PMC_22118463","title":"Lin28A 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Protein-RNA interaction of LIN28-let-7.","date":"2021","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34883291","citation_count":22,"is_preprint":false},{"pmid":"36428779","id":"PMC_36428779","title":"Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36428779","citation_count":22,"is_preprint":false},{"pmid":"26692113","id":"PMC_26692113","title":"LIN28: A Stem Cell Factor with a Key Role in Pediatric Tumor Formation.","date":"2016","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/26692113","citation_count":22,"is_preprint":false},{"pmid":"30481289","id":"PMC_30481289","title":"Dppa3 is critical for Lin28a-regulated ES cells naïve-primed state conversion.","date":"2019","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30481289","citation_count":22,"is_preprint":false},{"pmid":"26910839","id":"PMC_26910839","title":"MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26910839","citation_count":21,"is_preprint":false},{"pmid":"31747721","id":"PMC_31747721","title":"LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four-centre case-control study.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31747721","citation_count":21,"is_preprint":false},{"pmid":"34628272","id":"PMC_34628272","title":"LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury.","date":"2021","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/34628272","citation_count":20,"is_preprint":false},{"pmid":"33443086","id":"PMC_33443086","title":"BMP4 activates the Wnt-Lin28A-Blimp1-Wnt pathway to promote primordial germ cell formation via altering H3K4me2.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33443086","citation_count":20,"is_preprint":false},{"pmid":"30956008","id":"PMC_30956008","title":"The Long Non-Coding RNA lep-5 Promotes the Juvenile-to-Adult Transition by Destabilizing LIN-28.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/30956008","citation_count":20,"is_preprint":false},{"pmid":"29758178","id":"PMC_29758178","title":"Lin28a regulates neurogliogenesis in mammalian retina through the Igf signaling.","date":"2018","source":"Developmental 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research","url":"https://pubmed.ncbi.nlm.nih.gov/30531691","citation_count":19,"is_preprint":false},{"pmid":"31574415","id":"PMC_31574415","title":"LIN28: A cancer stem cell promoter for immunotherapy in head and neck squamous cell carcinoma.","date":"2019","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31574415","citation_count":18,"is_preprint":false},{"pmid":"30423261","id":"PMC_30423261","title":"The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30423261","citation_count":18,"is_preprint":false},{"pmid":"27693787","id":"PMC_27693787","title":"Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27693787","citation_count":18,"is_preprint":false},{"pmid":"25188417","id":"PMC_25188417","title":"LIN28A expression reduces sickling of cultured human erythrocytes.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25188417","citation_count":18,"is_preprint":false},{"pmid":"24631505","id":"PMC_24631505","title":"Reversible acetylation of Lin28 mediated by PCAF and SIRT1.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24631505","citation_count":18,"is_preprint":false},{"pmid":"24963666","id":"PMC_24963666","title":"Lin-28 regulates oogenesis and muscle formation in Drosophila melanogaster.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24963666","citation_count":17,"is_preprint":false},{"pmid":"26944953","id":"PMC_26944953","title":"Lin28A and androgen receptor expression in ER-/Her2+ breast cancer.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/26944953","citation_count":16,"is_preprint":false},{"pmid":"33504840","id":"PMC_33504840","title":"Identification of RNA-binding proteins that partner with Lin28a to regulate Dnmt3a expression.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33504840","citation_count":16,"is_preprint":false},{"pmid":"37124491","id":"PMC_37124491","title":"Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37124491","citation_count":16,"is_preprint":false},{"pmid":"31712708","id":"PMC_31712708","title":"FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31712708","citation_count":16,"is_preprint":false},{"pmid":"27730721","id":"PMC_27730721","title":"LIN-28 balances longevity and germline stem cell number in Caenorhabditis elegans through let-7/AKT/DAF-16 axis.","date":"2016","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/27730721","citation_count":16,"is_preprint":false},{"pmid":"35806250","id":"PMC_35806250","title":"LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806250","citation_count":15,"is_preprint":false},{"pmid":"32333719","id":"PMC_32333719","title":"SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32333719","citation_count":15,"is_preprint":false},{"pmid":"30883865","id":"PMC_30883865","title":"Lin28a expression protects against streptozotocin-induced β-cell destruction and prevents diabetes in mice.","date":"2019","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/30883865","citation_count":15,"is_preprint":false},{"pmid":"31637712","id":"PMC_31637712","title":"Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31637712","citation_count":15,"is_preprint":false},{"pmid":"30137214","id":"PMC_30137214","title":"HMGA2 is regulated by LIN28 and BRCA1 in human placental cells.","date":"2019","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/30137214","citation_count":15,"is_preprint":false},{"pmid":"37188880","id":"PMC_37188880","title":"Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37188880","citation_count":14,"is_preprint":false},{"pmid":"34868981","id":"PMC_34868981","title":"Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34868981","citation_count":13,"is_preprint":false},{"pmid":"28179426","id":"PMC_28179426","title":"Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28179426","citation_count":13,"is_preprint":false},{"pmid":"31338973","id":"PMC_31338973","title":"LIN28A gene polymorphisms confer Wilms tumour susceptibility: A four-centre case-control study.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31338973","citation_count":13,"is_preprint":false},{"pmid":"34380031","id":"PMC_34380031","title":"Non-microRNA binding competitively inhibits LIN28 regulation.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34380031","citation_count":12,"is_preprint":false},{"pmid":"36436798","id":"PMC_36436798","title":"Lin28a induced mitochondrial dysfunction in human granulosa cells via suppressing LARS2 expression.","date":"2022","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/36436798","citation_count":12,"is_preprint":false},{"pmid":"36382664","id":"PMC_36382664","title":"LncRNA DDX11-AS1 Promotes Chemoresistance through LIN28A-Mediated ATG12 mRNA Stabilization in Breast Cancer.","date":"2022","source":"Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36382664","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46488,"output_tokens":7380,"usd":0.125082,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16714,"output_tokens":6004,"usd":0.116835,"stage2_stop_reason":"end_turn"},"total_usd":0.241917,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"LIN28A recruits the TUTase Zcchc11/TUT4 to precursor let-7 in the cytoplasm, inducing polyuridylation that blocks Dicer processing. This mechanism is distinct from LIN28B, which acts in the nucleus by sequestering primary let-7 transcripts and inhibiting Microprocessor processing in a Zcchc11-independent manner.\",\n      \"method\": \"Zcchc11 depletion, subcellular fractionation, functional assays in cancer cell lines and xenografts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, localization, functional rescue), replicated across multiple cell lines and in vivo xenografts, mechanistically distinguishes LIN28A vs LIN28B pathways\",\n      \"pmids\": [\"22118463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans LIN-28 directly binds precursor let-7 miRNA to prevent Dicer processing, and stimulates uridylation of pre-let-7 by the poly(U) polymerase PUP-2 in vitro. LIN-28 and PUP-2 interact directly, establishing the conserved uridylation-based mechanism for let-7 suppression.\",\n      \"method\": \"In vitro uridylation assay, direct binding assays, C. elegans genetics, in vivo functional experiments\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of uridylation, direct protein-RNA and protein-protein interaction assays, genetic validation in vivo\",\n      \"pmids\": [\"19713957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Lin-28 binds IGF-2 mRNA and associates with polysomes and translation initiation complexes in skeletal myoblasts, increasing translational efficiency of IGF-2. Lin-28 was also found in stress granules (stalled mRNA-protein translation complexes), supporting its role as a translational enhancer.\",\n      \"method\": \"RNA immunoprecipitation, polysome fractionation, loss-of-function and gain-of-function assays in cultured myoblasts, biochemical co-fractionation, stress granule localization\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated by biochemical pulldown, polysome association, functional rescue assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17473174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LIN28A represses miR-9 precursor processing through a uridylation-independent mechanism during neuronal differentiation, reducing mature miR-9 levels and thereby controlling differentiation capacity of P19 cells.\",\n      \"method\": \"P19 cell differentiation assay, inducible LIN28A expression system, miRNA processing assays, loss-of-function experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible and constitutive expression systems with multiple readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"24722317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The E3 ligase Trim25 binds the conserved terminal loop of pre-let-7 and acts as an RNA-specific cofactor that activates TUT4, enabling more efficient Lin28A-mediated uridylation of pre-let-7. This cofactor specificity explains why, despite Lin28A binding many pre-miRNAs, only pre-let-7 is efficiently uridylated.\",\n      \"method\": \"RNA pulldown coupled with quantitative mass spectrometry, RNA binding assays, TuT4 activity assays, identification of Trim25 as cofactor\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — RNA pulldown with quantitative MS to identify cofactor, functional validation of uridylation enhancement, mechanistic in vitro assays in single rigorous study\",\n      \"pmids\": [\"25457611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LIN28 CSD recognizes a (U)GAU motif on pre-let-7, partitioning let-7 family members into CSD+ and CSD- subclasses. CSD+ precursors undergo more efficient in vivo recognition, 3′ uridylation, and degradation, resulting in stronger suppression in LIN28-activated cells.\",\n      \"method\": \"Single-nucleotide-resolution in vivo CLIP mapping of LIN28 binding sites, analysis of uridylation and degradation of let-7 subclasses\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — single-nucleotide resolution CLIP-seq with functional validation of differential suppression, rigorous mechanistic dissection of CSD binding motif\",\n      \"pmids\": [\"30029005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PCAF directly interacts with and acetylates Lin28 at the cold shock domain (CSD), leading to reduced Lin28 protein levels and increased mature let-7a. SIRT1 reverses this acetylation. The PCAF/SIRT1 balance regulates Lin28 activity in let-7a biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, domain mapping, SIRT1 deacetylation assay, let-7a level measurement\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro acetylation assay, co-IP for interaction, domain mapping to CSD, functional consequence on let-7a levels; multiple orthogonal methods in single study\",\n      \"pmids\": [\"24631505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERK1/2 kinases directly phosphorylate Lin28a at Ser-200. Phospho-mimetic (S200D) Lin28a shows impaired inhibition of let-7 miRNA and decreased cyclin D1; phospho-deficient (S200A) Lin28a expresses less let-7, proliferates faster, and exhibits a differentiation defect. ERK-mediated phosphorylation thus modulates Lin28a's ability to suppress let-7 and regulate pluripotency.\",\n      \"method\": \"In vitro kinase assay, CRISPR/Cas9 knock-in of S200A and S200D mutants in P19 cells, let-7 miRNA measurement, proliferation and differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus CRISPR knock-in of phospho-mutants with functional readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28179426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP28, a deubiquitinating enzyme, interacts with LIN28A and reverses its proteasomal ubiquitination-dependent degradation, thereby stabilizing LIN28A protein and extending its half-life. USP28-mediated stabilization of LIN28A enhances cancer cell viability and migration.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life measurement, cancer cell functional assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for interaction, ubiquitination assay, functional consequence on protein stability and cell phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"30543854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LIN28A is SUMOylated in vivo and in vitro at Lys-15, a modification that increases its binding affinity for pre-let-7, enhances TUT4 recruitment, and blocks DICER processing, thereby amplifying suppression of mature let-7. SUMOylation is increased by hypoxia and reduced by chemotherapy drugs (Cisplatin, Paclitaxel). A K15R SUMOylation-deficient mutant abolishes these effects.\",\n      \"method\": \"In vivo and in vitro SUMOylation assays, mutagenesis (K15R), pre-let-7 binding affinity assay, TUT4 recruitment assay, DICER processing assay, in vivo tumor growth assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro and in vivo SUMOylation with site mutagenesis, direct binding affinity measurement, mechanistic dissection of TUT4 recruitment and DICER blockade; multiple orthogonal methods in single study\",\n      \"pmids\": [\"32333719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lin28a directly binds Pck2 mRNA (mitochondrial phosphoenolpyruvate carboxykinase 2) and increases its transcript level. Cardiac-specific deletion of Lin28a attenuates pressure overload-induced hypertrophy; increasing Pck2 is sufficient to promote hypertrophic growth similar to Lin28a overexpression; epistatic analysis shows Pck2 mediates Lin28a's role in cardiac hypertrophic growth and glycolytic reprogramming.\",\n      \"method\": \"RNA immunoprecipitation, cardiac-specific Lin28a knockout, transverse aortic constriction model, epistasis analysis, metabolomic analysis, Pck2 knockdown/overexpression\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-IP for direct mRNA binding, cardiac-specific KO with defined phenotype, epistasis with Pck2, metabolomics; multiple orthogonal methods, in vivo and in vitro\",\n      \"pmids\": [\"30636447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN28 binds small nucleolar RNAs (snoRNAs) and rRNA to maintain nucleolar integrity. LIN28 resides in a complex with Nucleolin (NCL) and the transcriptional repressor TRIM28 at the Dux and rDNA loci. Loss of LIN28 causes nucleolar phase separation defects, ribosomal stress, P53 activation, and de-repression of the 2C transcription factor Dux.\",\n      \"method\": \"Chromatin immunoprecipitation, RNA binding assays for snoRNAs/rRNA, co-immunoprecipitation of NCL/TRIM28 complex, LIN28 knockout in pluripotent stem cells, nucleolar imaging\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for complex, ChIP for locus occupancy, KO with defined nucleolar and transcriptional phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34331666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lin28a directly binds the mRNA of Lars2 (mitochondrial leucyl-tRNA synthetase) and suppresses its translation. Overexpression of LARS2 reversed Lin28a-induced estrogen downregulation and mitochondrial dysfunction in human granulosa cells.\",\n      \"method\": \"RNA immunoprecipitation for direct mRNA binding, LARS2 overexpression rescue, measurement of estrogen, ATP, mitochondrial membrane potential in LIN28A overexpression/knockdown cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP confirming direct binding, rescue experiment establishing epistasis; single lab, two orthogonal methods\",\n      \"pmids\": [\"36436798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN28A directly binds the GGAGA motif in the promoter region of CENPE mRNA (as shown by RIP, RNA pulldown, and dual luciferase reporter assays), promoting CENPE expression and thereby sustaining proliferation and chemoresistance in AML cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pulldown, dual luciferase reporter assay, CENPE knockdown rescue, AML cell proliferation and apoptosis assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + RNA pulldown + luciferase reporter, functional rescue by CENPE KD; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34868981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LIN28A recruits RNA-binding protein MSI2 via its CSD domain (interacting with MSI2's RRM domain) to directly induce mRNA decay of YAP1 upstream kinases (MST1/2 and LATS1/2), inhibiting the Hippo pathway and activating YAP1 to promote cancer stem cell properties, independently of let-7.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (CSD of LIN28 and RRM of MSI2), transcriptome analysis, LIN28A/MSI2 knockdown with YAP1 constitutive activation rescue, mRNA stability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, transcriptome analysis, in vivo xenograft rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35102250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lin28 loss-of-function in C. elegans uses two distinct steps: first, a let-7-independent positive regulation of hbl-1 through its 3′ UTR to control L2 stage cell fates; second, a let-7-dependent step controlling subsequent fates via repression of lin-41. This two-step mechanism is separable by genetics.\",\n      \"method\": \"C. elegans genetic epistasis, let-7 pathway double mutants, lin-28/let-7/lin-41 genetic interaction analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis in multiple double-mutant combinations demonstrating two separable mechanistic activities, replicated across multiple alleles\",\n      \"pmids\": [\"22457637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNA-IP sequencing in cardiomyocytes identified long noncoding RNA H19 as the most significantly altered LIN28a target after injury. Ablation of H19 blunted LIN28a-induced enhancement of cardiomyocyte metabolism and cell cycle activity, placing H19 downstream of LIN28a in cardiac repair.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq) from LIN28a-overexpressing cardiomyocytes after injury, H19 ablation rescue assay, cell cycle and metabolism assays\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq for direct target identification, functional epistasis via H19 ablation; single lab, two orthogonal methods\",\n      \"pmids\": [\"36314132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lin28a overexpression in Drosophila intestinal stem cells boosts insulin signaling by increasing translation of Insulin-like Receptor (InR) mRNA, promoting symmetric division and stem cell expansion. Forced expression of InR completely rescues lin-28 null mutant defects in stem cell number and division pattern. This stem cell activity is independent of let-7.\",\n      \"method\": \"Drosophila lin-28 null mutant analysis, immunoprecipitation of Lin-28-bound mRNAs, InR forced expression rescue, lin-28/let-7 epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA immunoprecipitation identifying InR as target, genetic rescue demonstrating epistasis, let-7 independence confirmed; single lab, multiple methods\",\n      \"pmids\": [\"26487778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LIN28A expression in sickle cell erythrocytes increases fetal hemoglobin (HbF), reduces beta(sickle)-globin expression, and strongly suppresses all members of the let-7 miRNA family, reducing sickling morphology without impairing differentiation or enucleation.\",\n      \"method\": \"Lentiviral LIN28A transgenic expression in CD34+ sickle cells, measurement of HbF, beta-globin, let-7 levels, erythrocyte morphology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct LIN28A overexpression with let-7 measurement and phenotypic rescue; single lab, mechanistically links LIN28A to let-7 suppression and globin switching\",\n      \"pmids\": [\"25188417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lin28a-containing high-molecular-weight complexes in mouse ESCs include helicases Ddx3x and other RNA-binding proteins (Hnrnph1, Hnrnpu, Syncrip). Suppression of Ddx3x, Hnrnph1, Hnrnpu, or Syncrip interferes with Lin28a binding to Dnmt3a mRNA, demonstrating that these proteins form an oligomeric RNP complex required for Lin28a-mediated translational regulation of Dnmt3a, independently of let-7.\",\n      \"method\": \"Purification of Lin28a-containing complexes, proteomic identification of interactors, RNAi-mediated knockdown of candidates, RNA immunoprecipitation of Lin28a-Dnmt3a mRNA interaction\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex purification with proteomics, RNAi epistasis confirming each partner's requirement for mRNA binding; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33504840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lin28 proteins directly bind a conserved element in the 3′ UTR of Hmga2 mRNA, causing down-regulation of its translation in differentiating ESCs, independently of let-7. This let-7-independent mechanism prevents inappropriate accumulation of Hmga2 and aberrant proliferation/apoptosis.\",\n      \"method\": \"RNA immunoprecipitation for Lin28-Hmga2 3′UTR binding, let-7-independent translational regulation assay, Hmga2 protein measurement in Lin28 knockdown/overexpression cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP demonstrating direct binding plus functional consequence on Hmga2 protein levels; single lab, two methods\",\n      \"pmids\": [\"27920151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN28 binding is ~99% to non-miRNA transcripts (protein-coding and ribosomal RNAs), and these non-miRNA binding sites are specific and strong but do not mediate direct post-transcriptional regulation. Instead, they sequester LIN28 protein, reducing its functional availability to regulate let-7 miRNA biogenesis.\",\n      \"method\": \"Transcriptome-wide CLIP-seq mapping of LIN28 binding sites, quantification of miRNA vs. non-miRNA binding proportions, functional assessment of let-7 regulation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide single-nucleotide CLIP mapping, quantitative analysis of binding proportions and functional consequence; single lab, rigorous single study\",\n      \"pmids\": [\"34380031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RKIP suppresses LIN28 transcription via inhibition of MAPK signaling, which leads to decreased Myc-driven LIN28 transcription. Suppression of LIN28 enables let-7 processing, which in turn inhibits HMGA2. LIN28 depletion and let-7 expression suppress bone metastasis; LIN28 re-expression restores bone metastasis in RKIP-expressing cells.\",\n      \"method\": \"Epistasis via LIN28 depletion/rescue in breast cancer cells and orthotopic murine model, MAPK inhibition, let-7 measurement, HMGA2 quantification\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo epistasis with LIN28 depletion and rescue in murine model, pathway validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19153603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The small molecule N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide blocks LIN28/let-7 interaction (confirmed by FRET assay), rescues let-7 processing and function in Lin28-expressing cancer cells, and a biotinylated derivative captures Lin28 from cell lysates, confirming on-target engagement.\",\n      \"method\": \"Protein/RNA FRET assay screening, biotinylated derivative pulldown from cell lysates, let-7 processing assay in cancer cells, tumor sphere formation assay, ESC differentiation assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical FRET inhibition, pulldown from cells confirming target engagement, functional rescue of let-7; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27548809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIN28A loss-of-function variant (R192G) causes developmental defects and Parkinson's disease-related phenotypes in midbrain dopamine neurons derived from patient iPSCs. Conditional Lin28 knockout in mice leads to midbrain dopamine neuron degeneration and PD-related behavioral deficits. Wild-type Lin28A expression rescues R192G phenotypes.\",\n      \"method\": \"Lin28 conditional knockout mice, isogenic hESC/hiPSC-based disease model with R192G variant, neuronal differentiation assays, cell transplantation in PD model rats with behavioral testing\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in mice, isogenic patient iPSC model with rescue by WT LIN28A, transplantation in rat PD model; multiple orthogonal in vivo methods\",\n      \"pmids\": [\"31750563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LIN28A knockdown in human trophoblast cells (ACH-3P) results in increased spontaneous syncytialization and upregulation of syncytiotrophoblast markers (hCG, LGALS13, ERVW-1), demonstrating that LIN28A has a functional role in restricting trophoblast differentiation in human but not mouse trophoblast stem cells.\",\n      \"method\": \"shRNA-mediated LIN28A knockdown, mRNA degradation targeting, syncytialization assay, syncytiotrophoblast marker quantification in ACH-3P and mTS cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific KD with defined differentiation phenotype and marker upregulation; single lab, two methods (shRNA + targeted mRNA degradation)\",\n      \"pmids\": [\"24006280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LIN28A binds the promoter region GGAGA motif of CENPE and also stabilizes mRNAs such as ATG12 (as shown for LIN28A in the context of DDX11-AS1-mediated chemoresistance). LIN28A stabilizes ATG7 and ATG12 mRNA by increasing their mRNA stability.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, Western blot for ATG7/ATG12\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay and mRNA stability assay, single lab; limited mechanistic detail on direct binding vs indirect stabilization\",\n      \"pmids\": [\"36382664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MeCP2 binds to methylated CpG islands at the LIN28A promoter and suppresses LIN28A transcription. MeCP2 knockdown transcriptionally activates LIN28A expression. LIN28A expression level is directly associated with CpG methylation status of two promoter-region CpG islands.\",\n      \"method\": \"Bisulfite sequencing, ChIP assay for MeCP2 at LIN28A promoter, MeCP2 knockdown, 5-Aza-CdR treatment, LIN28A mRNA/protein measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct MeCP2 binding, bisulfite sequencing of methylation state, functional knockdown; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26910839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIN28A is a bipartite RNA-binding protein (cold shock domain + zinc knuckle domain) that acts primarily in the cytoplasm to block let-7 miRNA biogenesis by binding pre-let-7 and recruiting the TUTase TUT4/Zcchc11 (facilitated by the cofactor Trim25) to polyuridylate the precursor, targeting it for degradation; its CSD recognizes a (U)GAU motif partitioning let-7 precursors into high- and low-efficiency suppression subclasses, while ~99% of its binding occurs on non-miRNA transcripts that sequester its activity; post-translationally, LIN28A is acetylated by PCAF (reversed by SIRT1), phosphorylated by ERK1/2 at Ser-200 to impair let-7 suppression, SUMOylated at Lys-15 to enhance let-7 suppression and TUT4 recruitment, ubiquitinated for proteasomal degradation (reversed by USP28), and also acts in let-7-independent modes by directly binding and regulating translation or stability of specific mRNAs including IGF-2, Pck2, Hmga2, Dnmt3a, Lars2, and H19, in some cases within oligomeric RNP complexes; in the nucleus, LIN28A associates with snoRNAs/rRNA and a Nucleolin/TRIM28 complex to maintain nucleolar integrity and repress the 2C transcriptional program.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIN28A is a bipartite RNA-binding protein that governs cell fate, proliferation, and metabolic programs primarily by blocking biogenesis of the let-7 family of microRNAs [#0, #1]. In the cytoplasm it binds precursor let-7 and recruits the terminal uridylyltransferase TUT4/Zcchc11 to polyuridylate the precursor and block Dicer processing — a conserved mechanism reconstituted from C. elegans LIN-28/PUP-2 to human cells, and mechanistically distinct from the nuclear, uridylation-independent route used by LIN28B [#0, #1]. Selectivity for let-7 among many bound pre-miRNAs is conferred at two levels: the E3 ligase Trim25 binds the pre-let-7 terminal loop to activate TUT4 [#4], and the cold-shock domain recognizes a (U)GAU motif that partitions let-7 members into efficiently versus poorly suppressed subclasses [#5]; meanwhile the large majority of LIN28A binding occurs on non-miRNA transcripts that sequester the protein away from let-7 regulation [#21]. This let-7 axis is tuned by an extensive set of post-translational modifications: PCAF acetylates the CSD to destabilize LIN28A and is reversed by SIRT1 [#6], ERK1/2 phosphorylates Ser-200 to impair let-7 suppression [#7], SUMOylation at Lys-15 enhances pre-let-7 binding and TUT4 recruitment [#9], and USP28-mediated deubiquitination stabilizes the protein against proteasomal turnover [#8]. LIN28A also acts independently of let-7 by directly binding specific transcripts to control their translation or stability — enhancing IGF-2 [#2] and InR [#17] translation, repressing Hmga2 [#20] and Lars2 [#12], regulating Dnmt3a within an oligomeric RNP containing Ddx3x, Hnrnph1, Hnrnpu and Syncrip [#19], inducing decay of Hippo-pathway kinase mRNAs via MSI2 to activate YAP1 [#14], and acting through Pck2 and the lncRNA H19 in cardiac growth and repair [#10, #16]. In the nucleus it associates with snoRNAs/rRNA and a Nucleolin/TRIM28 complex to maintain nucleolar integrity and repress the 2C/Dux program [#11]. A loss-of-function R192G variant causes midbrain dopamine neuron degeneration and Parkinson's-related phenotypes, rescued by wild-type LIN28A [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the first molecular activity of Lin-28 — direct binding of a target mRNA to enhance its translation — defining it as a positive translational regulator before the let-7 connection was known.\",\n      \"evidence\": \"RNA-IP, polysome fractionation, and gain/loss-of-function in myoblasts showing IGF-2 binding and stress-granule localization\",\n      \"pmids\": [\"17473174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address let-7 or miRNA biogenesis\", \"Mechanism of translational enhancement not resolved at nucleotide level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the conserved core mechanism of let-7 suppression by showing LIN-28 binds pre-let-7 and directly stimulates its uridylation by a poly(U) polymerase.\",\n      \"evidence\": \"In vitro uridylation reconstitution, direct binding assays, and C. elegans genetics with PUP-2\",\n      \"pmids\": [\"19713957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human TUTase identity not established here\", \"Cofactor requirements for specificity unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed LIN28 within an oncogenic signaling circuit by showing it is a MAPK/Myc-driven transcriptional output whose suppression unleashes let-7 to block metastasis.\",\n      \"evidence\": \"LIN28 depletion/rescue epistasis in breast cancer cells and orthotopic murine model with let-7 and HMGA2 readouts\",\n      \"pmids\": [\"19153603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect transcriptional regulation, not direct LIN28 activity\", \"Did not dissect which let-7 targets drive metastasis\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the human mechanism and distinguished LIN28A from LIN28B, showing LIN28A recruits TUT4/Zcchc11 to cytoplasmic pre-let-7 whereas LIN28B acts nuclearly and TUTase-independently.\",\n      \"evidence\": \"Zcchc11 depletion, subcellular fractionation, and functional rescue across cancer cell lines and xenografts\",\n      \"pmids\": [\"22118463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how only let-7 is selected among bound pre-miRNAs\", \"Regulation of TUT4 recruitment unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Separated LIN28's let-7-dependent and let-7-independent activities genetically, showing it controls successive developmental cell fates through two distinct mechanisms.\",\n      \"evidence\": \"C. elegans epistasis with let-7/lin-41 and hbl-1 3'UTR regulation across multiple alleles\",\n      \"pmids\": [\"22457637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of hbl-1 3'UTR regulation not defined\", \"Mammalian equivalence of two-step model not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Explained let-7 selectivity by identifying Trim25 as an RNA-specific cofactor that activates TUT4 on the pre-let-7 terminal loop.\",\n      \"evidence\": \"RNA pulldown with quantitative mass spectrometry and in vitro TUT4 activity assays\",\n      \"pmids\": [\"25457611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Trim25 loop recognition unresolved\", \"Whether Trim25 acts on let-7-independent targets unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Opened the post-translational regulation of LIN28A by showing acetylation (PCAF) and phosphorylation (ERK1/2 at Ser-200) modulate its stability and let-7-suppressing activity.\",\n      \"evidence\": \"In vitro acetylation/kinase assays, domain mapping, SIRT1 reversal, and CRISPR phospho-mutant knock-ins with functional readouts\",\n      \"pmids\": [\"24631505\", \"28179426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals integrating these modifications in vivo not mapped\", \"Crosstalk between modifications not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the let-7-independent translational mechanism to mammalian stem-cell programs, showing direct binding of Hmga2 and InR transcripts controls differentiation and stem-cell expansion.\",\n      \"evidence\": \"RNA-IP and genetic rescue in differentiating ESCs (Hmga2) and Drosophila intestinal stem cells (InR)\",\n      \"pmids\": [\"27920151\", \"26487778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-site determinants of let-7-independent targets not generalized\", \"How target choice is partitioned from let-7 activity unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated druggability and validated the LIN28/let-7 interaction as the on-target node using a small-molecule inhibitor.\",\n      \"evidence\": \"FRET-based inhibition screen, biotinylated-probe pulldown, and let-7 rescue in cancer cells\",\n      \"pmids\": [\"27548809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity over let-7-independent functions not tested\", \"In vivo efficacy not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the sequence logic of CSD recognition, showing a (U)GAU motif sorts let-7 precursors into high- and low-efficiency suppression subclasses.\",\n      \"evidence\": \"Single-nucleotide-resolution in vivo CLIP with uridylation and degradation analysis of let-7 subclasses\",\n      \"pmids\": [\"30029005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of subclass partitioning across tissues unmapped\", \"Interplay with Trim25 loop recognition not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified deubiquitination as a stability control point, with USP28 reversing proteasomal turnover to extend LIN28A half-life and promote cancer phenotypes.\",\n      \"evidence\": \"Co-IP, ubiquitination and protein half-life assays, and cancer cell functional readouts\",\n      \"pmids\": [\"30543854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase driving ubiquitination not identified\", \"Single-lab two-method evidence for the interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked LIN28A to a Mendelian-relevant neurodegenerative phenotype, showing an R192G loss-of-function variant drives midbrain dopamine neuron degeneration rescuable by wild-type protein.\",\n      \"evidence\": \"Conditional KO mice, isogenic patient iPSC model with WT rescue, and transplantation in a rat PD model\",\n      \"pmids\": [\"31750563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target whose dysregulation by R192G causes degeneration not defined\", \"Whether let-7 or let-7-independent activity mediates the phenotype unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a let-7-independent metabolic role, showing direct Pck2 mRNA binding mediates cardiac hypertrophic growth and glycolytic reprogramming.\",\n      \"evidence\": \"RNA-IP, cardiac-specific KO, transverse aortic constriction, epistasis, and metabolomics\",\n      \"pmids\": [\"30636447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LIN28A increases Pck2 transcript level mechanistically unclear\", \"Generalizability beyond cardiac tissue untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added SUMOylation at Lys-15 as an activating modification that boosts pre-let-7 binding and TUT4 recruitment, linking stress signals to let-7 suppression.\",\n      \"evidence\": \"In vivo/in vitro SUMOylation assays, K15R mutagenesis, binding affinity and DICER processing assays, and tumor growth model\",\n      \"pmids\": [\"32333719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase and protease enzymes not identified\", \"Crosstalk with phosphorylation/acetylation marks unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a nuclear/nucleolar function distinct from let-7, showing LIN28 binds snoRNAs/rRNA and resides in an NCL/TRIM28 complex maintaining nucleolar integrity and repressing the 2C/Dux program.\",\n      \"evidence\": \"ChIP, snoRNA/rRNA binding assays, NCL/TRIM28 co-IP, and KO with nucleolar imaging in pluripotent stem cells\",\n      \"pmids\": [\"34331666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role in phase separation unresolved\", \"Single-lab evidence for the NCL/TRIM28 complex\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed binding stoichiometry by showing ~99% of LIN28 binding is to non-miRNA transcripts that sequester the protein rather than being directly regulated.\",\n      \"evidence\": \"Transcriptome-wide single-nucleotide CLIP with quantification of miRNA vs non-miRNA binding and let-7 functional assessment\",\n      \"pmids\": [\"34380031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sequestration is dynamically regulated unknown\", \"Reconciliation with documented functional mRNA targets not fully addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LIN28A as a subunit of oligomeric RNP complexes required for let-7-independent mRNA regulation, with multiple RNA-binding partners needed for target engagement.\",\n      \"evidence\": \"Complex purification, proteomics, and RNAi epistasis showing Ddx3x/Hnrnph1/Hnrnpu/Syncrip are required for Lin28a binding to Dnmt3a mRNA\",\n      \"pmids\": [\"33504840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Architecture and stoichiometry of the RNP not resolved\", \"Whether the same complex serves other targets unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a let-7-independent oncogenic mechanism in which LIN28A recruits MSI2 to degrade Hippo-pathway kinase mRNAs, activating YAP1 and cancer stem-cell properties.\",\n      \"evidence\": \"Co-IP with CSD/RRM domain mapping, transcriptome analysis, mRNA stability assays, and YAP1 rescue in xenografts\",\n      \"pmids\": [\"35102250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to kinase mRNAs vs MSI2-bridged binding not fully separated\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended let-7-independent control to noncoding RNA and additional metabolic targets, placing H19 and Lars2 downstream of LIN28A in cardiac repair and ovarian mitochondrial function.\",\n      \"evidence\": \"RIP-seq/RNA-IP for direct binding and ablation/overexpression rescue (H19 in cardiomyocytes; Lars2 in granulosa cells)\",\n      \"pmids\": [\"36314132\", \"36436798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-site features distinguishing these targets not defined\", \"Single-lab two-method evidence each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LIN28A integrates its parallel modifications and partitions activity between let-7 suppression, sequestration on abundant non-miRNA RNAs, and diverse let-7-independent mRNA/ncRNA targets within a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to target choice\", \"Structural basis of simultaneous CSD/zinc-knuckle target recognition across target classes lacking\", \"Which activity drives the R192G neurodegeneration phenotype unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10, 12, 16, 19, 20, 21]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 17, 19, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 4, 5, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 17, 19, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 17, 18, 24, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 22, 24]}\n    ],\n    \"complexes\": [\n      \"LIN28A-TUT4/Zcchc11-Trim25 uridylation complex\",\n      \"Lin28a-Ddx3x/Hnrnph1/Hnrnpu/Syncrip RNP\",\n      \"LIN28-Nucleolin-TRIM28 nucleolar complex\"\n    ],\n    \"partners\": [\"TUT4\", \"TRIM25\", \"PCAF\", \"SIRT1\", \"USP28\", \"MSI2\", \"NCL\", \"DDX3X\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}