{"gene":"HNRNPLL","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2008,"finding":"hnRNPLL was identified as a critical inducible regulator of CD45 alternative splicing in T cells. It is up-regulated upon T cell stimulation, binds CD45 pre-mRNA transcripts, and is both necessary and sufficient for activation-induced skipping of CD45 variable exons (generating the CD45RO isoform from CD45RA). Depletion or overexpression in B and T cell lines and primary T cells reciprocally altered CD45RA and RO expression. Exon array analysis indicated hnRNPLL acts as a global regulator of alternative splicing in activated T cells.","method":"shRNA interference screen, overexpression, RNA binding assays, exon array analysis, flow cytometry for CD45 isoforms","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (shRNA screen, overexpression, RNA binding, exon array) in primary cells and cell lines; foundational paper replicated by independent labs","pmids":["18669861"],"is_preprint":false},{"year":2008,"finding":"A single point mutation in hnRNPLL destabilizes its RNA-recognition domain, which normally binds with micromolar affinity to RNA containing the Ptprc (CD45) exon-silencing sequence. This mutation selectively diminished T cell accumulation in peripheral lymphoid tissues without affecting proliferation, and abrogated the extensive program of alternative mRNA splicing in memory T cells coordinated by hnRNPLL.","method":"ENU mutagenesis screen, RRM domain binding assay (micromolar affinity measurement), exon-array analysis of mutant naive and memory T cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical binding affinity measurement combined with in vivo mutant phenotype and genome-wide splicing analysis","pmids":["19100700"],"is_preprint":false},{"year":2008,"finding":"hnRNP LL (hnRNPLL) was identified via a cell-based screen as a distinct signal-induced repressor of CD45 variable exon 4. Its expression and binding to the ESS1 exonic splicing silencer element are up-regulated upon T cell activation. hnRNPLL overexpression increases exon repression; knockdown eliminates activation-induced exon skipping. hnRNPLL has overlapping but distinct binding requirements compared to hnRNP L at ESS1.","method":"Cell-based screen for splicing regulators, microarray, overexpression, knockdown, RNA-protein binding assays with ESS1 mutants","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 — cell-based screen with gain- and loss-of-function validation and direct RNA-binding characterization; independent corroboration of Oberdoerffer 2008","pmids":["18719244"],"is_preprint":false},{"year":2012,"finding":"In plasma cells, hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in membrane-encoding Ighg2b isoform at the expense of the secreted isoform (opposing ELL2 function). hnRNPLL also alters splicing of CD44 pre-mRNA in plasma cells, promoting variable exon inclusion and decreasing overall CD44 expression.","method":"lentiviral shRNA screen, transcriptional profiling, RNA immunoprecipitation, RNA-Seq, isoform-specific RT-PCR","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — RNA-IP with isoform analysis and shRNA knockdown validated across multiple targets","pmids":["22991471"],"is_preprint":false},{"year":2014,"finding":"hnRNPLL induces retention of specific introns in polyadenylated mRNA, including introns flanking variable exons 4–6 of Ptprc (CD45). In T cells with an inactivating Hnrpll mutation, these introns are no longer retained. A similar pattern of hnRNPLL-induced differential intron retention flanking alternative exons was identified in 14 other genes. Retroviral re-expression of a normally spliced cDNA of one target, Senp2, partially rescued the survival defect of Hnrpll-mutant T cells, placing Senp2 downstream of hnRNPLL.","method":"Deep sequencing of polyadenylated RNA from Hnrpll-mutant T cells and B cells with low Hnrpll; retroviral rescue experiment","journal":"Genome Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis rescue experiment combined with genome-wide RNA-seq; multiple independent analytical approaches","pmids":["24476532"],"is_preprint":false},{"year":2015,"finding":"hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3' UTRs of target RNAs in plasma cells (identified by PAR-CLIP). It promotes exon inclusion or exclusion in a context-dependent manner and stabilizes mRNA when associated with 3' UTRs. During B cell to plasma cell differentiation, hnRNPLL mediates a genome-wide switch of RNA processing, leading to loss of Bcl6 expression and increased Ig production.","method":"PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation), RNA sequencing, primary B cell to plasma cell differentiation assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 — PAR-CLIP defines binding motif (CA dinucleotides) with genome-wide resolution; orthogonal RNA-seq validation in primary differentiating cells","pmids":["25825742"],"is_preprint":false},{"year":2017,"finding":"hnRNPLL specifically associates with cytoplasmic poly(A)-binding protein PABPC1 in both T cells and plasma cells (co-immunoprecipitation). PABPC1 is not required for hnRNPLL-mediated alternative splicing of CD45, but promotes hnRNPLL binding to immunoglobulin mRNA and regulates switching from membrane IgH to secreted IgH, likely via mRNA alternative polyadenylation.","method":"Co-immunoprecipitation, RNA immunoprecipitation, isoform-specific RT-PCR, knockdown of PABPC1","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal co-IP with functional follow-up by knockdown and isoform analysis in two cell types; single lab","pmids":["28611064"],"is_preprint":false},{"year":2017,"finding":"HNRNPLL knockdown enhanced invasion activity of colon cancer cells in vitro and metastatic ability in vivo. RNA immunoprecipitation showed HNRNPLL binds CD44 pre-mRNA; knockdown increased CD44 variable exon 6 (Cd44v6) levels, and a neutralizing CD44v6 antibody suppressed the invasion induced by HNRNPLL knockdown. HNRNPLL expression was down-regulated during EMT, defining a HNRNPLL–CD44v6 axis in colorectal cancer metastasis suppression.","method":"Genome-wide shRNA library screen in vivo (rectal implantation syngeneic mouse model), RNA immunoprecipitation, Matrigel invasion assay, neutralizing antibody rescue","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — in vivo shRNA screen validated by RNA-IP, functional invasion assay, and antibody epistasis rescue","pmids":["28360095"],"is_preprint":false},{"year":2018,"finding":"An alternative HNRNPLL transcript variant containing an additional exon 12A (E12A) is generated by ADAR1/ADAR2-mediated A-to-I RNA editing. ADAR editing of exon 12A creates an enhancer for the splicing factor SRSF1, thereby promoting inclusion of E12A via splicing. The E12A isoform regulates a distinct set of growth-related genes (including CCND1 and TGFBR1) compared to canonical HNRNPLL; silencing E12A impairs clonogenic ability and enhances sensitivity to doxorubicin.","method":"RNA-seq, ADAR knockdown/overexpression, splicing reporter assays, SRSF1 binding analysis, clonogenic assay, drug sensitivity assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods in single lab establishing the ADAR-SRSF1-E12A regulatory axis","pmids":["29769310"],"is_preprint":false},{"year":2018,"finding":"HNRNPLL stabilizes mRNAs encoding DNA replication factors PCNA, RFC3, and FEN1 in colorectal cancer cells, promoting cell cycle progression and proliferation. RNA immunoprecipitation demonstrated direct binding of HNRNPLL to these mRNAs. HNRNPLL overexpression suppressed actinomycin D-induced degradation of these transcripts, and knockdown of any single target (PCNA, RFC3, or FEN1) suppressed the proliferative effect of HNRNPLL overexpression.","method":"RNA immunoprecipitation, actinomycin D mRNA stability assay, RNA-seq, knockdown epistasis experiments, cell proliferation assay","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-IP with mRNA stability assay and downstream epistasis, single lab","pmids":["29869816"],"is_preprint":false},{"year":2020,"finding":"hnRNPLL controls exit from pluripotency in embryonic stem cells by promoting ES cell-preferred exon skipping events upon onset of differentiation. hnRNPLL depletion leads to sustained expression of ES cell-preferred isoforms of Bptf and Tbx3, causing differentiation deficiency, developmental defects, and growth impairment in hnRNPLL-KO mice.","method":"Bioinformatic screening combined with functional RBP knockdown/knockout, alternative splicing analysis by RNA-seq, hnRNPLL knockout mice","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined developmental phenotype plus genome-wide splicing analysis and specific isoform validation","pmids":["33349972"],"is_preprint":false},{"year":2011,"finding":"hnRNPLL acts as a trans-acting factor required for alternative splicing of the Ptprc mRNA (silencing of CD45 RA, RB, and RC exons) in both conventional T cells and NKT cells equally. However, hnRNPLL is required for survival of conventional T cells but not NKT cells, revealing divergent functions beyond splicing regulation.","method":"Analysis of Hnrpllthunder point mutation in mice, flow cytometry, CD45 isoform analysis by RT-PCR, cell number and functional assays in NKT vs conventional T cells","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mutant mouse with cell-type comparison and direct molecular readout of Ptprc splicing","pmids":["22073166"],"is_preprint":false},{"year":2021,"finding":"In plasmablasts, hnRNPLL mutation disrupts alternative splicing of Ptprc, preventing downregulation of B220 (high-molecular-weight CD45 isoforms persist). However, this dysregulation of Ptprc splicing does not affect B cell development, mature B cell subsets, B cell proliferation, or in vitro plasmablast generation. The germinal center B cell defect in Hnrnpllthu/thu mice is B cell extrinsic.","method":"Mixed bone marrow chimera analysis, in vitro B cell stimulation and differentiation assays, CD45 isoform analysis, immunization experiments","journal":"Immunology and Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 — bone marrow chimera establishes cell-extrinsic mechanism; multiple stimulation conditions tested","pmids":["33331104"],"is_preprint":false},{"year":2023,"finding":"A lncRNA (lnc-PPP2R1B) physically interacts with and stabilizes HNRNPLL protein. This interaction promotes HNRNPLL-mediated alternative splicing of PPP2R1B pre-mRNA, retaining exons 2 and 3, which preserves PP2A enzyme function, enhances dephosphorylation and nuclear translocation of β-catenin, and thereby promotes osteogenesis of mesenchymal stem cells.","method":"RNA immunoprecipitation, lncRNA overexpression/knockdown, HNRNPLL knockdown, alternative splicing analysis, PP2A activity assay, β-catenin nuclear translocation assay, in vivo ectopic osteogenesis","journal":"Stem Cell Reviews and Reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — lncRNA-protein interaction with functional splicing readout and pathway epistasis, single lab","pmids":["37243830"],"is_preprint":false},{"year":2024,"finding":"hnRNPLL regulates alternative splicing of myoferlin (MYOF) pre-mRNA in pancreatic ductal adenocarcinoma. hnRNPLL depletion stimulates MYOF exon 17 retention, reducing production of the short MYOF isoform (MYOFb) and inhibiting cancer cell migration and invasion. Overexpression of hnRNPLL or MYOFb promoted pancreatic cancer cell migration and invasion, placing MYOFb downstream of hnRNPLL in promoting early metastasis.","method":"RNA-seq (exon skipping analysis), hnRNPLL knockdown/overexpression, MYOFb overexpression rescue, migration and invasion assays","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional splicing target validated with gain- and loss-of-function and epistasis rescue in cancer cell lines","pmids":["39742990"],"is_preprint":false}],"current_model":"HNRNPLL is a tissue-specific RNA-binding protein that is induced upon lymphocyte activation and terminal differentiation; it recognizes CA-rich sequence elements in introns and 3' UTRs, promotes context-dependent exon inclusion or skipping (most notably silencing of CD45 variable exons via ESS1), stabilizes select mRNAs through 3' UTR binding, cooperates with PABPC1 to regulate immunoglobulin heavy-chain alternative polyadenylation, controls a global alternative splicing program in memory T cells, plasma cells, and embryonic stem cells (including Tbx3 and Bptf isoform switching for pluripotency exit), and suppresses colorectal cancer metastasis by repressing CD44v6 splicing, while in cancer contexts it can also stabilize pro-proliferative mRNAs (PCNA, RFC3, FEN1) and regulate MYOF splicing to promote invasion."},"narrative":{"teleology":[{"year":2008,"claim":"Two independent screens resolved the long-standing question of which trans-acting factor mediates activation-induced CD45 exon skipping in T cells, identifying HNRNPLL as an inducible repressor that binds the ESS1 silencer element and is both necessary and sufficient for the CD45RA-to-CD45RO switch.","evidence":"shRNA screens, overexpression, RNA-binding assays, exon array, and flow cytometry in primary human T cells and cell lines","pmids":["18669861","18719244"],"confidence":"High","gaps":["Precise structural basis of ESS1 recognition by HNRNPLL RRMs not determined","Mechanism by which T cell activation transcriptionally or post-transcriptionally upregulates HNRNPLL not defined"]},{"year":2008,"claim":"An ENU point mutation destabilizing the HNRNPLL RRM established that its RNA-binding activity is essential in vivo for a broad alternative splicing program in memory T cells and for peripheral T cell homeostasis, extending its role far beyond a single CD45 target.","evidence":"ENU mutagenesis screen in mice, RRM binding affinity measurement, exon-array profiling of mutant naive and memory T cells","pmids":["19100700"],"confidence":"High","gaps":["Specific splicing targets responsible for the T cell survival defect not fully delineated","Whether the peripheral accumulation defect reflects apoptosis, impaired proliferation, or altered homing not resolved"]},{"year":2012,"claim":"Demonstration that HNRNPLL regulates immunoglobulin heavy-chain isoform choice and CD44 splicing in plasma cells established it as a shared splicing regulator across both T and B lineage terminal differentiation.","evidence":"Lentiviral shRNA knockdown, RNA immunoprecipitation, RNA-seq, and isoform-specific RT-PCR in plasma cells","pmids":["22991471"],"confidence":"High","gaps":["Mechanism of HNRNPLL-mediated IgH membrane vs. secreted isoform selection not fully characterized"]},{"year":2014,"claim":"Deep RNA-seq of Hnrpll-mutant T cells revealed that HNRNPLL induces retention of specific introns flanking alternative exons—not only in Ptprc but in at least 14 other genes—and retroviral rescue of one target (Senp2) partially restored T cell survival, placing a specific downstream effector in the HNRNPLL pathway.","evidence":"Deep sequencing of polyadenylated RNA from Hnrpll-mutant T and B cells; retroviral Senp2 cDNA rescue","pmids":["24476532"],"confidence":"High","gaps":["Whether intron retention is a direct consequence of HNRNPLL binding or a secondary effect is not resolved for most targets","Relative contribution of Senp2 versus other targets to the survival phenotype unclear"]},{"year":2015,"claim":"PAR-CLIP defined the HNRNPLL binding landscape genome-wide, showing preferential recognition of CA-dinucleotide-rich sequences in introns and 3′ UTRs, and established that 3′ UTR binding stabilizes mRNAs—thereby demonstrating HNRNPLL has dual functions in splicing regulation and mRNA stability during B-to-plasma-cell differentiation.","evidence":"PAR-CLIP in plasma cells, RNA-seq, primary B-to-plasma-cell differentiation assay","pmids":["25825742"],"confidence":"High","gaps":["Structural basis for CA-repeat preference not determined","Mechanism by which 3′ UTR binding leads to mRNA stabilization (competition with decay factors?) not elucidated"]},{"year":2017,"claim":"Identification of PABPC1 as a cytoplasmic interaction partner of HNRNPLL revealed a cooperative mechanism for immunoglobulin mRNA processing: PABPC1 facilitates HNRNPLL binding to IgH transcripts and regulates membrane-to-secreted IgH switching, likely via alternative polyadenylation, while being dispensable for CD45 exon silencing.","evidence":"Co-immunoprecipitation, RNA immunoprecipitation, PABPC1 knockdown, isoform-specific RT-PCR in T cells and plasma cells","pmids":["28611064"],"confidence":"Medium","gaps":["Whether PABPC1–HNRNPLL interaction is direct or bridged by RNA not established","Alternative polyadenylation mechanism inferred but not directly demonstrated"]},{"year":2017,"claim":"An in vivo shRNA screen in a colorectal cancer metastasis model showed HNRNPLL suppresses invasion by repressing CD44v6 inclusion; this placed HNRNPLL in cancer biology and demonstrated that its splicing activity on CD44 pre-mRNA has phenotypic consequences for metastasis.","evidence":"Genome-wide shRNA library screen in syngeneic mouse rectal implantation model, RNA-IP, Matrigel invasion, anti-CD44v6 antibody rescue","pmids":["28360095"],"confidence":"High","gaps":["Mechanism linking EMT signals to HNRNPLL downregulation undefined","Whether CD44v6 is the sole mediator of metastasis suppression not fully tested"]},{"year":2018,"claim":"Discovery that ADAR1/2-mediated A-to-I editing of HNRNPLL exon 12A creates an SRSF1-dependent splicing enhancer revealed that HNRNPLL itself is subject to epitranscriptomic regulation, and the resulting E12A isoform controls a distinct set of growth-related genes (CCND1, TGFBR1).","evidence":"RNA-seq, ADAR knockdown/overexpression, splicing reporter, SRSF1 binding analysis, clonogenic and drug sensitivity assays","pmids":["29769310"],"confidence":"Medium","gaps":["Relative abundance and tissue distribution of E12A isoform not characterized","Whether E12A and canonical HNRNPLL have distinct RNA-binding specificities not tested"]},{"year":2018,"claim":"HNRNPLL was shown to stabilize PCNA, RFC3, and FEN1 mRNAs in colorectal cancer cells, promoting proliferation; epistasis experiments with individual target knockdowns confirmed these as downstream effectors, establishing a pro-proliferative mRNA stability function distinct from its splicing role.","evidence":"RNA-IP, actinomycin D mRNA decay assay, RNA-seq, knockdown epistasis, proliferation assays in CRC cells","pmids":["29869816"],"confidence":"Medium","gaps":["Whether mRNA stabilization occurs through 3′ UTR CA-element binding (as defined by PAR-CLIP) not confirmed for these specific targets","Relevance of this stabilization function in normal (non-cancer) cells untested"]},{"year":2020,"claim":"Knockout studies in mice and ES cells revealed that HNRNPLL controls exit from pluripotency by directing ES cell-preferred exon-skipping in Tbx3 and Bptf, extending its biological role beyond the immune system to fundamental developmental cell-fate decisions.","evidence":"HNRNPLL-KO mice, ES cell differentiation assays, RNA-seq alternative splicing analysis","pmids":["33349972"],"confidence":"High","gaps":["Mechanism by which HNRNPLL is upregulated at differentiation onset in ES cells undefined","Whether other hnRNP family members compensate partially in KO mice not addressed"]},{"year":2024,"claim":"HNRNPLL was found to regulate MYOF alternative splicing in pancreatic cancer, promoting the short MYOFb isoform that drives migration and invasion, revealing yet another cancer-relevant splicing target and demonstrating that HNRNPLL can function as a context-dependent pro-metastatic factor.","evidence":"RNA-seq exon-skipping analysis, HNRNPLL knockdown/overexpression, MYOFb rescue, migration and invasion assays in PDAC cell lines","pmids":["39742990"],"confidence":"Medium","gaps":["Direct binding of HNRNPLL to MYOF pre-mRNA not demonstrated by CLIP","In vivo metastasis validation not reported","How tissue context determines whether HNRNPLL is pro- or anti-metastatic (CRC vs. PDAC) not mechanistically explained"]},{"year":null,"claim":"Unresolved: the structural basis for CA-element recognition, the signaling pathways controlling HNRNPLL induction during activation and differentiation, and the rules determining whether HNRNPLL binding at a given site causes exon inclusion, exon skipping, intron retention, or mRNA stabilization remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of HNRNPLL RRM domains bound to RNA","Upstream regulators of HNRNPLL transcription and protein stability largely unknown","Decision rules for inclusion vs. skipping vs. stabilization at individual binding sites not modeled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,5,9]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,3,4,5,7,10,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3,4,5,7,10,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3,5,11,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10]}],"complexes":[],"partners":["PABPC1","SRSF1","ADAR1","ADAR2"],"other_free_text":[]},"mechanistic_narrative":"HNRNPLL is an RNA-binding protein that functions as a master regulator of alternative splicing programs during lymphocyte activation, terminal differentiation, and embryonic stem cell lineage commitment. It recognizes CA-rich elements in introns and 3′ UTRs via its RNA-recognition motifs, promoting context-dependent exon inclusion or skipping—most notably silencing CD45 (Ptprc) variable exons upon T cell activation to generate the CD45RO isoform—and stabilizing select mRNAs through 3′ UTR association [PMID:18669861, PMID:25825742, PMID:29869816]. Beyond immune cells, HNRNPLL controls pluripotency exit by directing ES cell-preferred exon-skipping events in targets such as Tbx3 and Bptf, and its loss causes developmental defects in knockout mice [PMID:33349972]. In cancer, HNRNPLL suppresses colorectal metastasis by repressing CD44v6 splicing and promotes pancreatic cancer invasion through MYOF alternative splicing, illustrating how its splicing targets dictate opposing phenotypic outcomes in different cellular contexts [PMID:28360095, PMID:39742990]."},"prefetch_data":{"uniprot":{"accession":"Q8WVV9","full_name":"Heterogeneous nuclear ribonucleoprotein L-like","aliases":["Stromal RNA-regulating factor"],"length_aa":542,"mass_kda":60.1,"function":"RNA-binding protein that functions as a regulator of alternative splicing for multiple target mRNAs, including PTPRC/CD45 and STAT5A. Required for alternative splicing of PTPRC","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8WVV9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPLL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HNRNPLL","total_profiled":1310},"omim":[{"mim_id":"611208","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN L-LIKE; HNRNPLL","url":"https://www.omim.org/entry/611208"},{"mim_id":"151460","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, C; PTPRC","url":"https://www.omim.org/entry/151460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPLL"},"hgnc":{"alias_symbol":[],"prev_symbol":["HNRPLL"]},"alphafold":{"accession":"Q8WVV9","domains":[{"cath_id":"3.30.70.330","chopping":"76-146","consensus_level":"high","plddt":89.3001,"start":76,"end":146},{"cath_id":"3.30.70.330","chopping":"167-257","consensus_level":"high","plddt":88.7749,"start":167,"end":257},{"cath_id":"3.30.70.330","chopping":"335-439","consensus_level":"high","plddt":93.234,"start":335,"end":439},{"cath_id":"3.30.70.330","chopping":"450-535","consensus_level":"high","plddt":92.1448,"start":450,"end":535}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVV9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVV9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVV9-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPLL","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPLL"},"sequence":{"accession":"Q8WVV9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WVV9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WVV9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVV9"}},"corpus_meta":[{"pmid":"18669861","id":"PMC_18669861","title":"Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18669861","citation_count":169,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19100700","id":"PMC_19100700","title":"Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL.","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19100700","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28360095","id":"PMC_28360095","title":"HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition.","date":"2017","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/28360095","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25825742","id":"PMC_25825742","title":"RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25825742","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24476532","id":"PMC_24476532","title":"The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA.","date":"2014","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/24476532","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22991471","id":"PMC_22991471","title":"Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22991471","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28611064","id":"PMC_28611064","title":"Cytoplasmic poly(A)-binding protein 1 (PABPC1) interacts with the RNA-binding protein hnRNPLL and thereby regulates immunoglobulin secretion in plasma cells.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28611064","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29769310","id":"PMC_29769310","title":"Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29769310","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33349972","id":"PMC_33349972","title":"hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33349972","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29869816","id":"PMC_29869816","title":"HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells.","date":"2018","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/29869816","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26821996","id":"PMC_26821996","title":"RNA-binding protein hnRNPLL as a critical regulator of lymphocyte homeostasis and differentiation.","date":"2016","source":"Wiley interdisciplinary reviews. 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(PMID:19100700)\",\n      \"pmids\": [\"18669861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A single point mutation destabilizing the RNA-recognition domain of hnRNPLL abolishes its micromolar-affinity binding to the Ptprc exon-silencing sequence, establishing that this RRM domain directly contacts the CD45 pre-mRNA to drive exon skipping in memory T cells.\",\n      \"method\": \"NMU mutagenesis screen, in vitro RNA-binding affinity measurement (NMR/ITC), exon array analysis of mutant vs. wild-type T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — point mutation combined with quantitative RNA-binding affinity measurement and functional exon-array validation\",\n      \"pmids\": [\"19100700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In plasma cells, hnRNPLL binds Ighg2b mRNA and promotes the membrane-encoding Ighg2b isoform at the expense of the secreted isoform; it also promotes inclusion of CD44 variable exons and reduces overall CD44 expression.\",\n      \"method\": \"shRNA knockdown, RNA-immunoprecipitation, RNA-seq, overexpression in plasmacytoma cell lines\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct RNA binding shown by RIP with functional isoform readout, single lab\",\n      \"pmids\": [\"22991471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPLL induces selective retention of introns flanking alternatively spliced exons in the Ptprc mRNA and 14 other genes in T cells; retroviral re-expression of properly spliced Senp2 cDNA partially rescues the survival defect of Hnrpll-mutant T cells, placing hnRNPLL-mediated Senp2 splicing upstream of T cell survival.\",\n      \"method\": \"Deep sequencing of polyadenylated RNA from Hnrpll-mutant vs. wild-type T cells; retroviral rescue experiment\",\n      \"journal\": \"Genome Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq with mutant allele plus genetic rescue, single lab\",\n      \"pmids\": [\"24476532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPLL preferentially binds CA dinucleotide-containing sequences in introns and 3′ UTRs (PAR-CLIP), promotes context-dependent exon inclusion or exclusion, stabilizes mRNAs when bound to 3′ UTRs, mediates loss of Bcl6 expression, and drives increased Ig production during B cell-to-plasma cell differentiation.\",\n      \"method\": \"PAR-CLIP, RNA-seq, knockdown in primary B cells differentiating to plasma cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — transcriptome-wide CLIP defining binding motif plus functional RNA-seq validation in primary cells, multiple orthogonal methods\",\n      \"pmids\": [\"25742825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPLL preferentially binds CA dinucleotide-containing sequences in introns and 3′ UTRs (PAR-CLIP), promotes context-dependent exon inclusion or exclusion, stabilizes mRNAs when bound to 3′ UTRs, mediates loss of Bcl6 expression, and drives increased Ig production during B cell-to-plasma cell differentiation.\",\n      \"method\": \"PAR-CLIP, RNA-seq, knockdown in primary B cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — PAR-CLIP defining CA-motif plus multi-method functional validation in primary cells\",\n      \"pmids\": [\"25825742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPLL physically associates with cytoplasmic PABPC1 in T cells and plasma cells; PABPC1 promotes hnRNPLL binding to immunoglobulin heavy-chain mRNA and is required for the switch from membrane to secreted IgH isoform, suggesting PABPC1 recruits hnRNPLL to the 3′ end of RNA to regulate alternative polyadenylation.\",\n      \"method\": \"Co-immunoprecipitation, RNA-immunoprecipitation, knockdown of PABPC1 with IgH isoform readout\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP plus functional knockdown, single lab\",\n      \"pmids\": [\"28611064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPLL binds CD44 pre-mRNAs in colorectal cancer cells; knockdown increases CD44 variable exon 6 (CD44v6) inclusion and enhances invasion; a neutralizing CD44v6 antibody suppresses the invasion induced by hnRNPLL knockdown, placing hnRNPLL upstream of CD44v6-driven invasion.\",\n      \"method\": \"shRNA library screen in vivo, RNA-immunoprecipitation, Matrigel invasion assay, antibody rescue\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA binding shown by RIP plus antibody epistasis rescue, single lab\",\n      \"pmids\": [\"28360095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An HNRNPLL transcript variant containing exon 12A (E12A) is generated by ADAR1/ADAR2-mediated A-to-I editing coupled with splicing; the edit creates an SRSF1 exonic splicing enhancer that promotes E12A inclusion, and E12A regulates a distinct set of growth-related genes (CCND1, TGFBR1) compared to canonical HNRNPLL.\",\n      \"method\": \"RNA-seq, ADAR knockdown/overexpression, minigene splicing assay, clonogenic assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between editing and splicing established with minigene and ADAR perturbation, single lab\",\n      \"pmids\": [\"29769310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNPLL binds mRNAs of DNA replication proteins PCNA, RFC3, and FEN1 via RNA-immunoprecipitation, stabilizes them (actinomycin D chase), and promotes cell cycle progression in colorectal cancer cells; knockdown of any single target reverses the proliferation effect.\",\n      \"method\": \"RNA-immunoprecipitation, actinomycin D mRNA stability assay, knockdown rescue\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct RNA binding plus mRNA stability measurement plus epistasis rescue, single lab\",\n      \"pmids\": [\"29869816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPLL promotes ES cell-preferred exon skipping events during the onset of differentiation; hnRNPLL-mediated alternative splicing of Bptf and Tbx3 transcription factors is required for pluripotency exit, as hnRNPLL KO sustains ES cell-preferred isoforms and causes differentiation deficiency and growth impairment in mice.\",\n      \"method\": \"Functional shRNA screen, hnRNPLL KO mice, RNA-seq, alternative splicing analysis\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with developmental phenotype and specific splicing targets identified, single lab\",\n      \"pmids\": [\"33349972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPLL is required as a trans-acting factor for alternative splicing of Ptprc in plasmablasts (silencing of exons 4-6); however, loss of this splicing regulation does not affect B cell development, activation, or plasma cell generation, demonstrating a cell-type-specific functional consequence for hnRNPLL-dependent CD45 splicing.\",\n      \"method\": \"Hnrnpll thunder mutant mice, mixed bone marrow chimeras, flow cytometry, in vitro B cell stimulation\",\n      \"journal\": \"Immunology and Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model with chimera controls and functional readouts, single lab\",\n      \"pmids\": [\"33331104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA lnc-PPP2R1B physically interacts with and stabilizes hnRNPLL protein; this interaction is required for hnRNPLL-mediated retention of exons 2 and 3 of PPP2R1B, which preserves PP2A enzyme function, promotes β-catenin dephosphorylation and nuclear translocation, and drives osteogenic differentiation of MSCs.\",\n      \"method\": \"RNA pulldown, Co-IP, knockdown of lnc-PPP2R1B and HNRNPLL, RT-PCR splicing assay, in vivo ectopic osteogenesis\",\n      \"journal\": \"Stem Cell Reviews and Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — physical interaction plus splicing readout plus downstream signaling pathway validated in vivo, single lab\",\n      \"pmids\": [\"37243830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPLL binds MYOF pre-mRNA and promotes exon 17 skipping to produce a short MYOF isoform (MYOFb); hnRNPLL depletion causes MYOF exon 17 retention, reduces MYOFb, and inhibits pancreatic cancer cell migration and invasion; overexpression of either hnRNPLL or MYOFb promotes metastatic behavior.\",\n      \"method\": \"Knockdown/overexpression, RNA-seq splicing analysis, migration/invasion assays\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional splicing target validated by isoform-specific rescue, single lab\",\n      \"pmids\": [\"39742990\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"hnRNPLL is an inducible nuclear RNA-binding protein that recognizes CA-rich motifs in introns and 3′ UTRs; upon induction in activated/terminally differentiated lymphocytes or during cell fate transitions, it drives context-dependent alternative exon skipping or inclusion (most notably CD45/Ptprc exons 4–6, CD44v6, Ig heavy chain, Bptf, Tbx3, MYOF), stabilizes specific mRNAs via 3′ UTR binding, and cooperates with PABPC1 to regulate alternative polyadenylation, collectively reprogramming transcriptomes to support lymphocyte differentiation, pluripotency exit, and cancer cell invasiveness.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"hnRNPLL was identified as a critical inducible regulator of CD45 alternative splicing in T cells. It is up-regulated upon T cell stimulation, binds CD45 pre-mRNA transcripts, and is both necessary and sufficient for activation-induced skipping of CD45 variable exons (generating the CD45RO isoform from CD45RA). Depletion or overexpression in B and T cell lines and primary T cells reciprocally altered CD45RA and RO expression. Exon array analysis indicated hnRNPLL acts as a global regulator of alternative splicing in activated T cells.\",\n      \"method\": \"shRNA interference screen, overexpression, RNA binding assays, exon array analysis, flow cytometry for CD45 isoforms\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (shRNA screen, overexpression, RNA binding, exon array) in primary cells and cell lines; foundational paper replicated by independent labs\",\n      \"pmids\": [\"18669861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A single point mutation in hnRNPLL destabilizes its RNA-recognition domain, which normally binds with micromolar affinity to RNA containing the Ptprc (CD45) exon-silencing sequence. This mutation selectively diminished T cell accumulation in peripheral lymphoid tissues without affecting proliferation, and abrogated the extensive program of alternative mRNA splicing in memory T cells coordinated by hnRNPLL.\",\n      \"method\": \"ENU mutagenesis screen, RRM domain binding assay (micromolar affinity measurement), exon-array analysis of mutant naive and memory T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical binding affinity measurement combined with in vivo mutant phenotype and genome-wide splicing analysis\",\n      \"pmids\": [\"19100700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hnRNP LL (hnRNPLL) was identified via a cell-based screen as a distinct signal-induced repressor of CD45 variable exon 4. Its expression and binding to the ESS1 exonic splicing silencer element are up-regulated upon T cell activation. hnRNPLL overexpression increases exon repression; knockdown eliminates activation-induced exon skipping. hnRNPLL has overlapping but distinct binding requirements compared to hnRNP L at ESS1.\",\n      \"method\": \"Cell-based screen for splicing regulators, microarray, overexpression, knockdown, RNA-protein binding assays with ESS1 mutants\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-based screen with gain- and loss-of-function validation and direct RNA-binding characterization; independent corroboration of Oberdoerffer 2008\",\n      \"pmids\": [\"18719244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In plasma cells, hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in membrane-encoding Ighg2b isoform at the expense of the secreted isoform (opposing ELL2 function). hnRNPLL also alters splicing of CD44 pre-mRNA in plasma cells, promoting variable exon inclusion and decreasing overall CD44 expression.\",\n      \"method\": \"lentiviral shRNA screen, transcriptional profiling, RNA immunoprecipitation, RNA-Seq, isoform-specific RT-PCR\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA-IP with isoform analysis and shRNA knockdown validated across multiple targets\",\n      \"pmids\": [\"22991471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPLL induces retention of specific introns in polyadenylated mRNA, including introns flanking variable exons 4–6 of Ptprc (CD45). In T cells with an inactivating Hnrpll mutation, these introns are no longer retained. A similar pattern of hnRNPLL-induced differential intron retention flanking alternative exons was identified in 14 other genes. Retroviral re-expression of a normally spliced cDNA of one target, Senp2, partially rescued the survival defect of Hnrpll-mutant T cells, placing Senp2 downstream of hnRNPLL.\",\n      \"method\": \"Deep sequencing of polyadenylated RNA from Hnrpll-mutant T cells and B cells with low Hnrpll; retroviral rescue experiment\",\n      \"journal\": \"Genome Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis rescue experiment combined with genome-wide RNA-seq; multiple independent analytical approaches\",\n      \"pmids\": [\"24476532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3' UTRs of target RNAs in plasma cells (identified by PAR-CLIP). It promotes exon inclusion or exclusion in a context-dependent manner and stabilizes mRNA when associated with 3' UTRs. During B cell to plasma cell differentiation, hnRNPLL mediates a genome-wide switch of RNA processing, leading to loss of Bcl6 expression and increased Ig production.\",\n      \"method\": \"PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation), RNA sequencing, primary B cell to plasma cell differentiation assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — PAR-CLIP defines binding motif (CA dinucleotides) with genome-wide resolution; orthogonal RNA-seq validation in primary differentiating cells\",\n      \"pmids\": [\"25825742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPLL specifically associates with cytoplasmic poly(A)-binding protein PABPC1 in both T cells and plasma cells (co-immunoprecipitation). PABPC1 is not required for hnRNPLL-mediated alternative splicing of CD45, but promotes hnRNPLL binding to immunoglobulin mRNA and regulates switching from membrane IgH to secreted IgH, likely via mRNA alternative polyadenylation.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, isoform-specific RT-PCR, knockdown of PABPC1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP with functional follow-up by knockdown and isoform analysis in two cell types; single lab\",\n      \"pmids\": [\"28611064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HNRNPLL knockdown enhanced invasion activity of colon cancer cells in vitro and metastatic ability in vivo. RNA immunoprecipitation showed HNRNPLL binds CD44 pre-mRNA; knockdown increased CD44 variable exon 6 (Cd44v6) levels, and a neutralizing CD44v6 antibody suppressed the invasion induced by HNRNPLL knockdown. HNRNPLL expression was down-regulated during EMT, defining a HNRNPLL–CD44v6 axis in colorectal cancer metastasis suppression.\",\n      \"method\": \"Genome-wide shRNA library screen in vivo (rectal implantation syngeneic mouse model), RNA immunoprecipitation, Matrigel invasion assay, neutralizing antibody rescue\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo shRNA screen validated by RNA-IP, functional invasion assay, and antibody epistasis rescue\",\n      \"pmids\": [\"28360095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An alternative HNRNPLL transcript variant containing an additional exon 12A (E12A) is generated by ADAR1/ADAR2-mediated A-to-I RNA editing. ADAR editing of exon 12A creates an enhancer for the splicing factor SRSF1, thereby promoting inclusion of E12A via splicing. The E12A isoform regulates a distinct set of growth-related genes (including CCND1 and TGFBR1) compared to canonical HNRNPLL; silencing E12A impairs clonogenic ability and enhances sensitivity to doxorubicin.\",\n      \"method\": \"RNA-seq, ADAR knockdown/overexpression, splicing reporter assays, SRSF1 binding analysis, clonogenic assay, drug sensitivity assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods in single lab establishing the ADAR-SRSF1-E12A regulatory axis\",\n      \"pmids\": [\"29769310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HNRNPLL stabilizes mRNAs encoding DNA replication factors PCNA, RFC3, and FEN1 in colorectal cancer cells, promoting cell cycle progression and proliferation. RNA immunoprecipitation demonstrated direct binding of HNRNPLL to these mRNAs. HNRNPLL overexpression suppressed actinomycin D-induced degradation of these transcripts, and knockdown of any single target (PCNA, RFC3, or FEN1) suppressed the proliferative effect of HNRNPLL overexpression.\",\n      \"method\": \"RNA immunoprecipitation, actinomycin D mRNA stability assay, RNA-seq, knockdown epistasis experiments, cell proliferation assay\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-IP with mRNA stability assay and downstream epistasis, single lab\",\n      \"pmids\": [\"29869816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPLL controls exit from pluripotency in embryonic stem cells by promoting ES cell-preferred exon skipping events upon onset of differentiation. hnRNPLL depletion leads to sustained expression of ES cell-preferred isoforms of Bptf and Tbx3, causing differentiation deficiency, developmental defects, and growth impairment in hnRNPLL-KO mice.\",\n      \"method\": \"Bioinformatic screening combined with functional RBP knockdown/knockout, alternative splicing analysis by RNA-seq, hnRNPLL knockout mice\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined developmental phenotype plus genome-wide splicing analysis and specific isoform validation\",\n      \"pmids\": [\"33349972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPLL acts as a trans-acting factor required for alternative splicing of the Ptprc mRNA (silencing of CD45 RA, RB, and RC exons) in both conventional T cells and NKT cells equally. However, hnRNPLL is required for survival of conventional T cells but not NKT cells, revealing divergent functions beyond splicing regulation.\",\n      \"method\": \"Analysis of Hnrpllthunder point mutation in mice, flow cytometry, CD45 isoform analysis by RT-PCR, cell number and functional assays in NKT vs conventional T cells\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant mouse with cell-type comparison and direct molecular readout of Ptprc splicing\",\n      \"pmids\": [\"22073166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In plasmablasts, hnRNPLL mutation disrupts alternative splicing of Ptprc, preventing downregulation of B220 (high-molecular-weight CD45 isoforms persist). However, this dysregulation of Ptprc splicing does not affect B cell development, mature B cell subsets, B cell proliferation, or in vitro plasmablast generation. The germinal center B cell defect in Hnrnpllthu/thu mice is B cell extrinsic.\",\n      \"method\": \"Mixed bone marrow chimera analysis, in vitro B cell stimulation and differentiation assays, CD45 isoform analysis, immunization experiments\",\n      \"journal\": \"Immunology and Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bone marrow chimera establishes cell-extrinsic mechanism; multiple stimulation conditions tested\",\n      \"pmids\": [\"33331104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A lncRNA (lnc-PPP2R1B) physically interacts with and stabilizes HNRNPLL protein. This interaction promotes HNRNPLL-mediated alternative splicing of PPP2R1B pre-mRNA, retaining exons 2 and 3, which preserves PP2A enzyme function, enhances dephosphorylation and nuclear translocation of β-catenin, and thereby promotes osteogenesis of mesenchymal stem cells.\",\n      \"method\": \"RNA immunoprecipitation, lncRNA overexpression/knockdown, HNRNPLL knockdown, alternative splicing analysis, PP2A activity assay, β-catenin nuclear translocation assay, in vivo ectopic osteogenesis\",\n      \"journal\": \"Stem Cell Reviews and Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — lncRNA-protein interaction with functional splicing readout and pathway epistasis, single lab\",\n      \"pmids\": [\"37243830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPLL regulates alternative splicing of myoferlin (MYOF) pre-mRNA in pancreatic ductal adenocarcinoma. hnRNPLL depletion stimulates MYOF exon 17 retention, reducing production of the short MYOF isoform (MYOFb) and inhibiting cancer cell migration and invasion. Overexpression of hnRNPLL or MYOFb promoted pancreatic cancer cell migration and invasion, placing MYOFb downstream of hnRNPLL in promoting early metastasis.\",\n      \"method\": \"RNA-seq (exon skipping analysis), hnRNPLL knockdown/overexpression, MYOFb overexpression rescue, migration and invasion assays\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional splicing target validated with gain- and loss-of-function and epistasis rescue in cancer cell lines\",\n      \"pmids\": [\"39742990\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPLL is a tissue-specific RNA-binding protein that is induced upon lymphocyte activation and terminal differentiation; it recognizes CA-rich sequence elements in introns and 3' UTRs, promotes context-dependent exon inclusion or skipping (most notably silencing of CD45 variable exons via ESS1), stabilizes select mRNAs through 3' UTR binding, cooperates with PABPC1 to regulate immunoglobulin heavy-chain alternative polyadenylation, controls a global alternative splicing program in memory T cells, plasma cells, and embryonic stem cells (including Tbx3 and Bptf isoform switching for pluripotency exit), and suppresses colorectal cancer metastasis by repressing CD44v6 splicing, while in cancer contexts it can also stabilize pro-proliferative mRNAs (PCNA, RFC3, FEN1) and regulate MYOF splicing to promote invasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HNRNPLL is an inducible RNA-binding protein that reprograms alternative splicing and mRNA stability during cell differentiation and activation, particularly in lymphocytes. It recognizes CA-rich motifs in introns and 3′ UTRs via its RNA recognition motif domain, driving context-dependent exon skipping or inclusion—most notably silencing CD45/Ptprc exons 4–6 to produce the CD45RO isoform in activated T cells, regulating immunoglobulin heavy-chain isoform switching in plasma cells, and controlling alternative splicing of Bptf and Tbx3 during pluripotency exit [PMID:18669861, PMID:25742825, PMID:33349972]. Beyond splicing, hnRNPLL stabilizes target mRNAs through 3′ UTR binding, cooperates with PABPC1 to regulate alternative polyadenylation of immunoglobulin transcripts, and its own expression is diversified through ADAR-mediated RNA editing that generates a functionally distinct exon 12A-containing isoform [PMID:25825742, PMID:28611064, PMID:29769310]. In cancer contexts, hnRNPLL modulates CD44 variable exon inclusion to control invasiveness and promotes proliferation by stabilizing DNA replication factor mRNAs including PCNA, RFC3, and FEN1 [PMID:28360095, PMID:29869816].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The discovery that hnRNPLL is an inducible trans-acting factor necessary and sufficient for CD45 exon skipping in T cells identified the first molecular function for this previously uncharacterized gene, explaining how T cells switch from CD45RA to CD45RO upon activation.\",\n      \"evidence\": \"shRNA screen, overexpression, RNA-IP, and loss-of-function in B/T cell lines and primary T cells; independently confirmed by ENU mutagenesis screen with quantitative RNA-binding measurements\",\n      \"pmids\": [\"18669861\", \"19100700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how the RRM domain selects exon-silencing sequences over other RNA targets was not resolved\", \"Whether hnRNPLL acts alone or requires co-factors for exon skipping was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending hnRNPLL function beyond T cells, its role in plasma cells was established: it binds Ighg2b mRNA to favor the membrane-encoding isoform and regulates CD44 variable exon inclusion, showing it acts on multiple transcripts during B lineage terminal differentiation.\",\n      \"evidence\": \"shRNA knockdown, RNA-IP, RNA-seq, and overexpression in plasmacytoma cell lines\",\n      \"pmids\": [\"22991471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The RNA elements mediating hnRNPLL binding on IgH and CD44 transcripts were not mapped\", \"Whether hnRNPLL regulates polyadenylation versus splicing of IgH was unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide analysis of hnRNPLL-mutant T cells revealed that hnRNPLL promotes selective intron retention flanking alternatively spliced exons in ~15 genes, and genetic rescue with Senp2 cDNA demonstrated that hnRNPLL-dependent splicing of specific targets is functionally linked to T cell survival.\",\n      \"evidence\": \"Deep RNA-seq of Hnrpll-mutant vs. wild-type T cells; retroviral Senp2 rescue experiment\",\n      \"pmids\": [\"24476532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intron retention represents a direct hnRNPLL binding event or an indirect consequence was not distinguished\", \"Contributions of individual target genes beyond Senp2 to the T cell phenotype remained unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Transcriptome-wide PAR-CLIP defined the hnRNPLL binding code as CA-rich sequences concentrated in introns and 3′ UTRs, and demonstrated a dual function: alternative splicing regulation when bound to introns and mRNA stabilization when bound to 3′ UTRs, collectively driving B cell-to-plasma cell differentiation including Bcl6 downregulation.\",\n      \"evidence\": \"PAR-CLIP, RNA-seq, and knockdown in primary differentiating B cells\",\n      \"pmids\": [\"25742825\", \"25825742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How hnRNPLL binding at 3′ UTRs mechanistically stabilizes mRNAs (e.g., competition with decay factors) was not determined\", \"The relative contributions of splicing versus stability regulation to plasma cell differentiation were not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The identification of PABPC1 as a physical partner that promotes hnRNPLL recruitment to immunoglobulin heavy-chain mRNA 3′ ends provided the first evidence for a cofactor-dependent mechanism by which hnRNPLL regulates alternative polyadenylation, expanding its functional repertoire beyond splicing and stability.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, RNA-IP, and PABPC1 knockdown with IgH isoform readout in T cells and plasma cells\",\n      \"pmids\": [\"28611064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PABPC1 and hnRNPLL form a direct binary complex or interact through RNA bridges was not resolved\", \"The generality of PABPC1-dependent hnRNPLL recruitment beyond IgH was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"hnRNPLL was shown to suppress CD44v6 inclusion in colorectal cancer cells, and antibody rescue experiments placed hnRNPLL upstream of CD44v6-driven invasion, establishing a cancer-relevant functional axis for hnRNPLL-mediated splicing.\",\n      \"evidence\": \"In vivo shRNA screen, RNA-IP, Matrigel invasion assay, anti-CD44v6 antibody epistasis rescue\",\n      \"pmids\": [\"28360095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How hnRNPLL distinguishes CD44 variable exons for inclusion vs. exclusion in different cell types was unresolved\", \"In vivo metastasis phenotype of hnRNPLL loss was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two new functional dimensions were uncovered: ADAR-mediated RNA editing generates a distinct hnRNPLL isoform (E12A) regulating growth genes, and hnRNPLL stabilizes mRNAs of DNA replication factors (PCNA, RFC3, FEN1) to promote cell cycle progression, broadening its role from lineage differentiation to proliferation control.\",\n      \"evidence\": \"ADAR knockdown/overexpression with minigene assay; RNA-IP plus actinomycin D stability chase with knockdown rescue in colorectal cancer cells\",\n      \"pmids\": [\"29769310\", \"29869816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the E12A isoform and canonical hnRNPLL have distinct RNA-binding specificities was not tested\", \"Structural basis for mRNA stabilization by hnRNPLL versus its splicing activity was not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"hnRNPLL was established as essential for pluripotency exit: it promotes ES cell-preferred exon skipping in Bptf and Tbx3 transcription factors, and hnRNPLL knockout mice display differentiation deficiency and growth impairment, demonstrating a developmental role beyond immune cells.\",\n      \"evidence\": \"Functional shRNA screen, hnRNPLL KO mice, RNA-seq with alternative splicing analysis\",\n      \"pmids\": [\"33349972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether hnRNPLL splicing targets in ES cells overlap with those in lymphocytes was not comprehensively compared\", \"The signaling cues inducing hnRNPLL during differentiation exit were not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Using Hnrpll-mutant mice, hnRNPLL was confirmed as the trans-acting factor for Ptprc exon silencing in plasmablasts, but loss of this regulation had no detectable impact on B cell development, activation, or plasma cell generation, revealing that hnRNPLL-dependent CD45 splicing is dispensable for B lineage function.\",\n      \"evidence\": \"Hnrpll thunder mutant mice, mixed bone marrow chimeras, flow cytometry, in vitro B cell stimulation\",\n      \"pmids\": [\"33331104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether compensatory mechanisms mask the functional consequence of persistent CD45RA in B lineage cells was not tested\", \"Broader hnRNPLL-dependent splicing events beyond Ptprc in B cells were not examined in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"hnRNPLL was shown to promote exon 17 skipping in MYOF to produce a pro-metastatic short isoform (MYOFb) in pancreatic cancer, with isoform-specific rescue confirming the splicing event as the functionally relevant output, further establishing hnRNPLL as a driver of cancer cell invasion through alternative splicing.\",\n      \"evidence\": \"Knockdown/overexpression, RNA-seq splicing analysis, migration and invasion assays with isoform-specific rescue\",\n      \"pmids\": [\"39742990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether hnRNPLL binds MYOF introns directly or acts indirectly was not shown by CLIP\", \"In vivo metastasis data for the hnRNPLL–MYOFb axis were not provided\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how hnRNPLL selects between exon skipping and exon inclusion on different targets, the structural basis for its dual roles in splicing regulation versus mRNA stabilization, and the upstream signaling pathways that control its induction during differentiation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of hnRNPLL bound to target RNA exists\", \"The determinants specifying exon inclusion versus exclusion remain unknown\", \"Upstream transcriptional and post-translational regulation of hnRNPLL induction is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 5, 9]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 4, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 10, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PABPC1\",\n      \"PTPRC\",\n      \"CD44\",\n      \"MYOF\",\n      \"ADAR1\",\n      \"ADAR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"HNRNPLL is an RNA-binding protein that functions as a master regulator of alternative splicing programs during lymphocyte activation, terminal differentiation, and embryonic stem cell lineage commitment. It recognizes CA-rich elements in introns and 3′ UTRs via its RNA-recognition motifs, promoting context-dependent exon inclusion or skipping—most notably silencing CD45 (Ptprc) variable exons upon T cell activation to generate the CD45RO isoform—and stabilizing select mRNAs through 3′ UTR association [PMID:18669861, PMID:25825742, PMID:29869816]. Beyond immune cells, HNRNPLL controls pluripotency exit by directing ES cell-preferred exon-skipping events in targets such as Tbx3 and Bptf, and its loss causes developmental defects in knockout mice [PMID:33349972]. In cancer, HNRNPLL suppresses colorectal metastasis by repressing CD44v6 splicing and promotes pancreatic cancer invasion through MYOF alternative splicing, illustrating how its splicing targets dictate opposing phenotypic outcomes in different cellular contexts [PMID:28360095, PMID:39742990].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Two independent screens resolved the long-standing question of which trans-acting factor mediates activation-induced CD45 exon skipping in T cells, identifying HNRNPLL as an inducible repressor that binds the ESS1 silencer element and is both necessary and sufficient for the CD45RA-to-CD45RO switch.\",\n      \"evidence\": \"shRNA screens, overexpression, RNA-binding assays, exon array, and flow cytometry in primary human T cells and cell lines\",\n      \"pmids\": [\"18669861\", \"18719244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise structural basis of ESS1 recognition by HNRNPLL RRMs not determined\",\n        \"Mechanism by which T cell activation transcriptionally or post-transcriptionally upregulates HNRNPLL not defined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An ENU point mutation destabilizing the HNRNPLL RRM established that its RNA-binding activity is essential in vivo for a broad alternative splicing program in memory T cells and for peripheral T cell homeostasis, extending its role far beyond a single CD45 target.\",\n      \"evidence\": \"ENU mutagenesis screen in mice, RRM binding affinity measurement, exon-array profiling of mutant naive and memory T cells\",\n      \"pmids\": [\"19100700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific splicing targets responsible for the T cell survival defect not fully delineated\",\n        \"Whether the peripheral accumulation defect reflects apoptosis, impaired proliferation, or altered homing not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that HNRNPLL regulates immunoglobulin heavy-chain isoform choice and CD44 splicing in plasma cells established it as a shared splicing regulator across both T and B lineage terminal differentiation.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, RNA immunoprecipitation, RNA-seq, and isoform-specific RT-PCR in plasma cells\",\n      \"pmids\": [\"22991471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of HNRNPLL-mediated IgH membrane vs. secreted isoform selection not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Deep RNA-seq of Hnrpll-mutant T cells revealed that HNRNPLL induces retention of specific introns flanking alternative exons—not only in Ptprc but in at least 14 other genes—and retroviral rescue of one target (Senp2) partially restored T cell survival, placing a specific downstream effector in the HNRNPLL pathway.\",\n      \"evidence\": \"Deep sequencing of polyadenylated RNA from Hnrpll-mutant T and B cells; retroviral Senp2 cDNA rescue\",\n      \"pmids\": [\"24476532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether intron retention is a direct consequence of HNRNPLL binding or a secondary effect is not resolved for most targets\",\n        \"Relative contribution of Senp2 versus other targets to the survival phenotype unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PAR-CLIP defined the HNRNPLL binding landscape genome-wide, showing preferential recognition of CA-dinucleotide-rich sequences in introns and 3′ UTRs, and established that 3′ UTR binding stabilizes mRNAs—thereby demonstrating HNRNPLL has dual functions in splicing regulation and mRNA stability during B-to-plasma-cell differentiation.\",\n      \"evidence\": \"PAR-CLIP in plasma cells, RNA-seq, primary B-to-plasma-cell differentiation assay\",\n      \"pmids\": [\"25825742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for CA-repeat preference not determined\",\n        \"Mechanism by which 3′ UTR binding leads to mRNA stabilization (competition with decay factors?) not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of PABPC1 as a cytoplasmic interaction partner of HNRNPLL revealed a cooperative mechanism for immunoglobulin mRNA processing: PABPC1 facilitates HNRNPLL binding to IgH transcripts and regulates membrane-to-secreted IgH switching, likely via alternative polyadenylation, while being dispensable for CD45 exon silencing.\",\n      \"evidence\": \"Co-immunoprecipitation, RNA immunoprecipitation, PABPC1 knockdown, isoform-specific RT-PCR in T cells and plasma cells\",\n      \"pmids\": [\"28611064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PABPC1–HNRNPLL interaction is direct or bridged by RNA not established\",\n        \"Alternative polyadenylation mechanism inferred but not directly demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"An in vivo shRNA screen in a colorectal cancer metastasis model showed HNRNPLL suppresses invasion by repressing CD44v6 inclusion; this placed HNRNPLL in cancer biology and demonstrated that its splicing activity on CD44 pre-mRNA has phenotypic consequences for metastasis.\",\n      \"evidence\": \"Genome-wide shRNA library screen in syngeneic mouse rectal implantation model, RNA-IP, Matrigel invasion, anti-CD44v6 antibody rescue\",\n      \"pmids\": [\"28360095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking EMT signals to HNRNPLL downregulation undefined\",\n        \"Whether CD44v6 is the sole mediator of metastasis suppression not fully tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that ADAR1/2-mediated A-to-I editing of HNRNPLL exon 12A creates an SRSF1-dependent splicing enhancer revealed that HNRNPLL itself is subject to epitranscriptomic regulation, and the resulting E12A isoform controls a distinct set of growth-related genes (CCND1, TGFBR1).\",\n      \"evidence\": \"RNA-seq, ADAR knockdown/overexpression, splicing reporter, SRSF1 binding analysis, clonogenic and drug sensitivity assays\",\n      \"pmids\": [\"29769310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative abundance and tissue distribution of E12A isoform not characterized\",\n        \"Whether E12A and canonical HNRNPLL have distinct RNA-binding specificities not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"HNRNPLL was shown to stabilize PCNA, RFC3, and FEN1 mRNAs in colorectal cancer cells, promoting proliferation; epistasis experiments with individual target knockdowns confirmed these as downstream effectors, establishing a pro-proliferative mRNA stability function distinct from its splicing role.\",\n      \"evidence\": \"RNA-IP, actinomycin D mRNA decay assay, RNA-seq, knockdown epistasis, proliferation assays in CRC cells\",\n      \"pmids\": [\"29869816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether mRNA stabilization occurs through 3′ UTR CA-element binding (as defined by PAR-CLIP) not confirmed for these specific targets\",\n        \"Relevance of this stabilization function in normal (non-cancer) cells untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Knockout studies in mice and ES cells revealed that HNRNPLL controls exit from pluripotency by directing ES cell-preferred exon-skipping in Tbx3 and Bptf, extending its biological role beyond the immune system to fundamental developmental cell-fate decisions.\",\n      \"evidence\": \"HNRNPLL-KO mice, ES cell differentiation assays, RNA-seq alternative splicing analysis\",\n      \"pmids\": [\"33349972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which HNRNPLL is upregulated at differentiation onset in ES cells undefined\",\n        \"Whether other hnRNP family members compensate partially in KO mice not addressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"HNRNPLL was found to regulate MYOF alternative splicing in pancreatic cancer, promoting the short MYOFb isoform that drives migration and invasion, revealing yet another cancer-relevant splicing target and demonstrating that HNRNPLL can function as a context-dependent pro-metastatic factor.\",\n      \"evidence\": \"RNA-seq exon-skipping analysis, HNRNPLL knockdown/overexpression, MYOFb rescue, migration and invasion assays in PDAC cell lines\",\n      \"pmids\": [\"39742990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of HNRNPLL to MYOF pre-mRNA not demonstrated by CLIP\",\n        \"In vivo metastasis validation not reported\",\n        \"How tissue context determines whether HNRNPLL is pro- or anti-metastatic (CRC vs. PDAC) not mechanistically explained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Unresolved: the structural basis for CA-element recognition, the signaling pathways controlling HNRNPLL induction during activation and differentiation, and the rules determining whether HNRNPLL binding at a given site causes exon inclusion, exon skipping, intron retention, or mRNA stabilization remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of HNRNPLL RRM domains bound to RNA\",\n        \"Upstream regulators of HNRNPLL transcription and protein stability largely unknown\",\n        \"Decision rules for inclusion vs. skipping vs. stabilization at individual binding sites not modeled\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 5, 9]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7, 10, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 7, 10, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3, 5, 11, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PABPC1\",\n      \"SRSF1\",\n      \"ADAR1\",\n      \"ADAR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}