{"gene":"HNRNPH1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2011,"finding":"hnRNPH controls alternative splicing of IG20/MADD (exon 16) and RON (exon 11) pre-mRNAs in glioblastoma, shifting splicing toward anti-apoptotic and pro-invasive isoforms; ablation of hnRNPH increases cell death and reduces invasiveness, phenotypes rescued by isoform-specific knockdown of the respective variants.","method":"siRNA knockdown, isoform-specific knockdown, splicing redirection, minigene assays in GBM cell lines","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional rescue experiments with two independent splicing targets, replicated across GBM specimens and cell lines","pmids":["21915099"],"is_preprint":false},{"year":2007,"finding":"hnRNPH binds G-rich enhancer sequences (M2) in PLP exon 3B and an intronic splicing enhancer (ISE) to promote DM20 5' splice site selection; knockdown of hnRNPH increases the PLP/DM20 ratio in oligodendrocytes, and combined knockdown of hnRNPH and hnRNPF has a synergistic effect mediated through the M2 element.","method":"siRNA knockdown in differentiated oligodendrocytes, mutagenesis of G-rich elements, minigene splicing assays, protein binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of binding sites combined with functional knockdown and multiple orthogonal assays","pmids":["17567613"],"is_preprint":false},{"year":2014,"finding":"hnRNPH binds G-rich sequences at the OPRM1 intronic SNP site (rs9479757); the G-to-A SNP transition weakens hnRNPH binding and causes exon 2 skipping, altering OPRM1 splice-variant mRNA and hMOR-1 protein levels in vitro and in human postmortem prefrontal cortex.","method":"EMSA (electrophoretic mobility shift assay), minigene splicing assay, siRNA knockdown, antisense morpholino oligonucleotide studies, human postmortem brain analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding demonstrated by EMSA, functional splicing confirmed by minigene and morpholino, validated in human tissue","pmids":["25122903"],"is_preprint":false},{"year":2015,"finding":"hnRNPH1 physically interacts with androgen receptor (AR) and steroid receptor coactivator-3 (SRC-3), and regulates expression of AR and its splice variant AR-V7; siRNA silencing of hnRNPH1 reduces AR and AR-V7 expression and sensitizes prostate cancer cells to bicalutamide.","method":"Co-immunoprecipitation, siRNA knockdown, ectopic expression of miR-212 mimics, in vivo prostate tumorigenesis assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for protein interactions, functional rescue experiments, single lab with multiple methods","pmids":["26553749"],"is_preprint":false},{"year":2015,"finding":"TALEN-mediated frameshift deletions in the first coding exon of Hnrnph1 (but not the neighboring gene Rufy1) recapitulate reduced methamphetamine-induced locomotor activity in mice, establishing Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity with a mechanism involving mesolimbic dopaminergic neurotransmission.","method":"TALEN gene editing, interval-specific congenic mouse lines, transcriptome analysis (mRNA-seq), behavioral pharmacology","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning confirmed by gene editing with negative control (Rufy1), replicated across congenic lines with transcriptomic mechanistic follow-up","pmids":["26658939"],"is_preprint":false},{"year":2016,"finding":"HNRNPH1 (and H2) bind exon 7 of Trf2 pre-mRNA and prevent production of the short TRF2-S isoform; HNRNPH silencing selectively elevates TRF2-S levels during neuronal differentiation, and CRISPR/Cas9-mediated deletion of hnRNPH2 accelerates NGF-triggered neuronal differentiation.","method":"Affinity pull-down, siRNA silencing, CRISPR/Cas9 deletion, isoform-specific RT-PCR, NGF differentiation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity pull-down identifies binding, functional silencing and CRISPR deletion with isoform phenotype, single lab","pmids":["27117401"],"is_preprint":false},{"year":2019,"finding":"HNRNPH1 (but not other homologous family members) facilitates exclusion of EWSR1 exon 8 from EWS-FLI1 pre-mRNA in Ewing sarcoma cells; this recruitment is driven by guanine-rich sequences within EWSR1 exon 8 capable of folding into RNA G-quadruplex structures, and an RNA G-quadruplex mimetic modulates HNRNPH1 binding and reduces growth of fusion-positive cells.","method":"Minigene splicing assay, siRNA knockdown, RNA pull-down, G-quadruplex RNA mimetic binding assay, cell growth assays, pyridostatin treatment","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding and functional specificity demonstrated with multiple orthogonal methods, mechanistic link between G4 sequences and HNRNPH1-dependent splicing","pmids":["31511320"],"is_preprint":false},{"year":2019,"finding":"Hnrnph1 heterozygous mutant mice show reduced methamphetamine reinforcement and intake, reduced methamphetamine-induced dopamine release in the nucleus accumbens, and a twofold increase in hnRNP H protein in striatal synaptosomes; synaptosomal proteomics revealed increased baseline mitochondrial complex I and V proteins in H1+/- mice that dynamically changed with methamphetamine administration.","method":"Operant self-administration, conditioned place preference, in vivo microdialysis, immunohistochemistry, immunoblot, synaptosomal proteomics (mass spectrometry)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal behavioral and neurochemical methods, protein-level mechanistic follow-up via proteomics, single lab but very comprehensive","pmids":["31704785"],"is_preprint":false},{"year":2019,"finding":"hnRNPH1 and PTBP1 cooperatively regulate TCF3 mutually exclusive alternative splicing: hnRNPH1 binds exonic splicing silencers (ESSs) in exon 18b while PTBP1 binds conserved intronic splicing silencers (ISSs) between the two mutually exclusive exons; position-dependent interactions between these factors are essential for proper MEAS.","method":"Minigene splicing assay, siRNA knockdown, RNA pull-down/EMSA for factor binding to ISSs and ESSs","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional binding and splicing assays with mutagenesis of binding sites, single lab","pmids":["31391218"],"is_preprint":false},{"year":2013,"finding":"hnRNPH1/H2 proteins bind a conserved G-rich sequence element within the U11-48K pre-mRNA and counteract activation of an alternative 3' splice site by U11 snRNP; knockdown of hnRNPH1/H2 or mutation of the G-run enhances 3' splice site activation, revealing a regulatory interplay between hnRNPH1/H2, U1 snRNP, and U11 snRNP.","method":"In vitro binding assays, siRNA knockdown, minigene splicing analysis, phylogenetic conservation analysis, mutation of G-run elements","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with functional knockdown and mutagenesis, single lab","pmids":["23335637"],"is_preprint":false},{"year":2021,"finding":"The LC1 low-complexity domain of hnRNPH1 undergoes reversible phase separation into polymers or liquid-like droplets, which is critical for interaction with other RNA-binding proteins and for alternative splicing activity; the LC2 domain does not contribute to phase separation but contributes to transcriptional activation when fused to a DNA-binding domain.","method":"Phase separation assays (in vitro droplet formation), domain deletion/mutation constructs, splicing reporter assays, transcriptional activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phase separation with functional splicing and transcription assays, single lab with domain-specific dissection","pmids":["34873036"],"is_preprint":false},{"year":2021,"finding":"hnRNPH1 binds the mRNA of PTPN6 and negatively regulates its expression; hnRNPH1 knockdown in CML cells increases PTPN6 levels, thereby suppressing PI3K/AKT activation and inhibiting cell proliferation while promoting apoptosis.","method":"RNA immunoprecipitation/pulldown, siRNA knockdown, western blot, in vitro and in vivo CML cell models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-binding shown by pulldown/RIP, functional pathway placement via knockdown and rescue, single lab","pmids":["34295818"],"is_preprint":false},{"year":2021,"finding":"hnRNPH1 associates with the RNA helicase MTR4/MTREX in an RNA-independent manner and localizes in nuclear speckles; depletion of hnRNPH1 enhances NEAT1v2 stability and promotes NEAT1v2-mediated IL8 mRNA expression, indicating hnRNPH1-MTR4 complex mediates NEAT1v2 degradation to control IL8.","method":"Co-immunoprecipitation (RNA-independent), RNA stability assays, siRNA knockdown, nuclear localization (imaging), IL8 mRNA measurement","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA-independent Co-IP establishes protein complex, functional knockdown with mechanistic pathway, single lab","pmids":["34470577"],"is_preprint":false},{"year":2022,"finding":"hnRNPH1 recruits PTBP2 and SRSF3 to modulate alternative splicing in germ cells; conditional knockout of Hnrnph1 in spermatogenic cells causes aberrant splicing of meiosis- and germ-Sertoli communication-related genes, asynapsis of chromosomes, and male and female sterility.","method":"Conditional knockout mice, RNA-seq splicing analysis, Co-immunoprecipitation for PTBP2/SRSF3 interaction, histology, fertility assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with transcriptome-wide splicing analysis and Co-IP for complex, replicated across male and female germ cell contexts","pmids":["35739118"],"is_preprint":false},{"year":2022,"finding":"HNRNPH1 binds EWSR1-exon 8 G-rich sequences with low nM affinity and destabilizes G-quadruplex (G4) structures formed by these sequences in a non-catalytic fashion, primarily through its qRRM1-qRRM2 domains; HNRNPH1 associates and dissociates faster from G4-folded RNA than from the same sequences in a non-G4 state, and binding favors accumulation of RNA in a non-G4 state to facilitate splicing regulation.","method":"Gel shift assays, spectroscopic assays (CD, NMR-related), biophysical binding measurements, domain-deletion constructs, minigene splicing, long-read sequencing","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with biophysical assays, mutagenesis (domain deletions), multiple orthogonal methods in single rigorous study","pmids":["35639772"],"is_preprint":false},{"year":2022,"finding":"SRSF3 and HNRNPH1 competitively bind to PRMT5 pre-mRNA at the region around the 3' splice site on intron 2 and the alternative 3' splice site on exon 4; IR-induced SRSF3 downregulation shifts the competitive balance toward HNRNPH1, increasing the PRMT5-ISO5 isoform level and enhancing tumor radiosensitivity.","method":"siRNA silencing of SRSF3 and HNRNPH1, RNA immunoprecipitation, minigene assays, in vivo xenograft irradiation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP demonstrates competitive binding, functional splicing changes with siRNA, in vivo validation, single lab","pmids":["36499164"],"is_preprint":false},{"year":2023,"finding":"HNRNPH1 mediates cold-dependent skipping of a poison exon in RBM3 pre-mRNA via a thermosensitive interaction with a G-rich motif within the poison exon; moderate hypothermia represses poison exon inclusion in an HNRNPH1-dependent manner, preventing NMD of RBM3 mRNA and enhancing RBM3 protein expression.","method":"Genome-wide CRISPR-Cas9 knockout screen in iPSC-derived neurons with RBM3 reporter, splicing analysis, HNRNPH1 knockdown, temperature-shift experiments, minigene assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — unbiased genome-wide screen identified HNRNPH1, mechanistic follow-up with minigene and thermosensitive binding, multiple orthogonal methods","pmids":["37248947"],"is_preprint":false},{"year":2023,"finding":"hnRNPH1 in Sertoli cells interacts with PTBP1 to regulate alternative splicing of target genes related to cell adhesion, and cooperates with androgen receptor (AR) to directly bind promoters of cell-cell junction and EGFR pathway genes and modulate their transcription; conditional knockout of hnRNPH1 in Sertoli cells disrupts blood-testis barrier, causes meiotic delay, germ cell apoptosis, and infertility.","method":"Conditional knockout mice (Sertoli cell-specific), Co-immunoprecipitation (hnRNPH1-PTBP1, hnRNPH1-AR), ChIP (promoter binding), RNA-seq, histology, fertility assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotype, reciprocal Co-IP for protein partners, ChIP for direct promoter binding, multiple orthogonal methods","pmids":["36718792"],"is_preprint":false},{"year":2023,"finding":"Murine knockin models of Hnrnph2 NLS mutations show that these mutations reduce interaction with the nuclear transport receptor Kapβ2 and cause cytoplasmic accumulation of hnRNPH2; Hnrnph2 knockout mice upregulate Hnrnph1 (genetic compensation), whereas knockin mice fail to upregulate Hnrnph1, establishing that HNRNPH1 can functionally substitute for HNRNPH2.","method":"Knockin and knockout mouse models, Co-IP for Kapβ2 interaction, immunofluorescence for localization, mRNA/protein quantification, behavioral phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple engineered mouse models with mechanistic biochemistry (Co-IP, localization), single lab but comprehensive genetic and molecular evidence","pmids":["37463454"],"is_preprint":false},{"year":2011,"finding":"hnRNPH1 physically interacts with the mature hepatitis C virus core protein (HCVc174); this interaction was confirmed by pull-down and confocal imaging, and colocalization shifts from cytoplasm+nucleus to cytoplasm only in cells with replicating HCV, indicating active viral replication confines this interaction to the cytoplasm.","method":"Affinity purification with LC-MS/MS proteomics, pull-down confirmation, confocal colocalization imaging","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pull-down and imaging confirm interaction, localization shift is functionally described, but mechanism of functional consequence not deeply resolved","pmids":["21823664"],"is_preprint":false},{"year":2021,"finding":"PRMT1-mediated arginine methylation of hnRNP H1 suppresses its binding to mRNAs of complement pathway components including C3; PRMT1-dependent methylation requires phosphorylation and reduces complement component expression in vitro; hepatocyte-specific PRMT1 knockout increases complement expression and systemic inflammation in alcohol-fed mice.","method":"Mass spectrometry for arginine methylation, RNA immunoprecipitation for mRNA binding, hepatocyte-specific PRMT1 knockout mice, in vitro expression assays","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified PTM, RIP for binding, KO mice with defined pathway phenotype, single lab","pmids":["34027271"],"is_preprint":false},{"year":2024,"finding":"PTK6 physically interacts with HNRNPH1 and phosphorylates it at tyrosine Y210, promoting HNRNPH1 liquid-liquid phase separation (LLPS); LLPS of HNRNPH1 triggers splicing-switching of NBR1 exon 10 inclusion, thereby activating autophagy and suppressing apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, phospho-site mutagenesis (Y210), FRAP, LLPS assays (liquid droplet imaging), minigene/splicing analysis, in vitro kinase assay, PDO and CDX models","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct phosphorylation by kinase with site-specific mutagenesis, FRAP for LLPS, functional splicing outcome linked to autophagy, single lab but multiple orthogonal methods","pmids":["40103198"],"is_preprint":false},{"year":2024,"finding":"hnRNPH1 functions as a pivotal mediator of mitochondrial retrograde signaling: under mitochondrial stress, hnRNPH1 accumulates in the nucleus via AMPK-dependent mechanism, interacts with transcription factor NRF1, and binds the DRP1 promoter to enhance DRP1 transcription; in the cytoplasm, hnRNPH1 directly interacts with DRP1 and enhances DRP1 Ser616 phosphorylation, triggering DRP1 translocation to mitochondria and mitochondrial fission.","method":"Subcellular fractionation, Co-immunoprecipitation, ChIP (DRP1 promoter binding), AMPK inhibition, phospho-specific western blot, mitochondrial morphology imaging","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and fractionation with functional consequence, single lab with multiple methods","pmids":["38898233"],"is_preprint":false},{"year":2024,"finding":"A conserved G-quadruplex within the polymerase coding region of yellow fever virus (orthoflavivirus) promotes viral replication and suppresses host stress responses via interactions with hnRNPH1; G4 binding to hnRNPH1 causes its cytoplasmic retention, impairing hnRNPH1 control of G4-containing tRNA fragments (tiRNAs) involved in stress-mediated translational reduction, thereby suppressing integrated stress responses and antiviral effects.","method":"Yellow fever virus infection, G4 identification, RNA pull-down for hnRNPH1 binding, subcellular fractionation (nuclear vs cytoplasmic localization), stress response assays, tiRNA analysis","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct G4-hnRNPH1 binding with functional localization change and defined pathway, single lab","pmids":["39094585"],"is_preprint":false},{"year":2024,"finding":"HNRNPH1 stabilizes FLOT2 mRNA in an m6A-dependent manner: HNRNPH1 interacts with METTL14 to prevent its STUB1-mediated degradation, leading to increased m6A modification on FLOT2 mRNA; IGF2BP3 then recognizes the m6A modification and further stabilizes FLOT2 mRNA. HNRNPH1 knockdown reduces FLOT2 expression and NPC cell proliferation/invasion.","method":"Co-immunoprecipitation (HNRNPH1-METTL14), RNA stability assays, m6A quantification, siRNA knockdown, rescue experiments with METTL14 re-expression, in vitro and in vivo NPC models","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, m6A assays, and functional rescue with defined pathway, single lab","pmids":["39570559"],"is_preprint":false},{"year":2024,"finding":"JEV nonstructural protein NS3 captures HNRNPH1 to recruit poly A-binding protein cytoplasmic 1 (PABPC1) and eukaryotic translation initiation factor 4F (eIF4F) complex, promoting viral replication; HNRNPH1 normally inhibits RIG-I/MDA5 signaling to decrease interferon expression, and SOX10 downregulates HNRNPH1 during JEV infection.","method":"Co-immunoprecipitation (NS3-HNRNPH1, HNRNPH1-PABPC1, HNRNPH1-eIF4F), siRNA knockdown, overexpression, IFN reporter assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP establishes interactions, functional knockdown/overexpression with defined viral and innate immune phenotypes, single lab","pmids":["39694377"],"is_preprint":false},{"year":2024,"finding":"hnRNPH1 suppresses influenza A virus (IAV) H1N1 and H9N2 replication by binding viral RNA of PB1, PA, and NP genes through its RRM1 and RRM2 domains and restraining viral polymerase activity; mutation of key tryptophan and tyrosine residues in RRM1 and RRM2 abolishes viral RNA binding and loss of polymerase suppression.","method":"Knockdown and overexpression in 293T cells, viral RNA binding assay, polymerase activity assay, site-directed mutagenesis of RRM domains","journal":"Microorganisms","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct RNA binding with active-site mutagenesis and functional polymerase assay, single lab","pmids":["39858792"],"is_preprint":false},{"year":2025,"finding":"HNRNPH1 interacts with IAV NS1 protein via the RBD domain of NS1 and the RRM and NLS regions of hnRNPH1; this interaction changes intracellular localization and splicing function of NS1, and HNRNPH1 interacts with p53 to regulate apoptosis; overexpression of hnRNPH1 decreases IAV multiplication while knockdown enhances replication.","method":"Co-immunoprecipitation, domain-mapping experiments (truncation mutants), subcellular localization assay, splicing assay, apoptosis assay, overexpression/knockdown","journal":"Emerging microbes & infections","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping, functional localization changes, multiple downstream assays, single lab","pmids":["40052960"],"is_preprint":false},{"year":2024,"finding":"BCAS2, hnRNPH1, and SRSF3 interact to form a complex that orchestrates alternative splicing of Trp53bp1 (53BP1), regulating DNA double-strand break repair during meiotic prophase I; conditional knockout of Bcas2 in germ cells impairs DSB repair and synapsis, and CLIP-seq mapped BCAS2 binding to 5' splice sites and GA-rich regions.","method":"Conditional knockout mice, CLIP-seq, Co-immunoprecipitation (BCAS2-hnRNPH1-SRSF3), splicing analysis, DSB repair assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq and Co-IP establish complex and binding sites, functional KO with defined meiotic phenotype, single lab","pmids":["39520542"],"is_preprint":false},{"year":2020,"finding":"Four 5' UTR variants in the DBA/2J allele of Hnrnph1 collectively reduce reporter expression in HEK293 and N2a cells and correspond to decreased 5' UTR usage and reduced hnRNP H protein levels in 114 kb congenic mice striatum, identifying these 5' UTR variants as quantitative trait variants (QTVs) underlying molecular regulation of Hnrnph1.","method":"Molecular cloning and reporter assay (5' UTR variants), exon-level transcriptome analysis, immunoblot, congenic mouse lines","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reporter assay for 5' UTR function, protein-level confirmation in vivo, single lab with multiple complementary approaches","pmids":["32401417"],"is_preprint":false},{"year":2020,"finding":"BL-associated TCF3 mutations reduce binding of hnRNPH1 to exon 18b ESS sequences, causing greater exon 18b inclusion and generating more of the mutated E47 isoform; upregulation of E47 dysregulates TCF3 targets PTPN6 and CCND3 involved in BL pathogenesis.","method":"RNA pull-down/EMSA (hnRNPH1 binding to WT vs. mutant exon 18b), minigene splicing assays, siRNA knockdown, qRT-PCR for TCF3 targets","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with mutant sequences, functional splicing assays, pathway-level follow-up, single lab","pmids":["32449435"],"is_preprint":false},{"year":2025,"finding":"HNRNPH1 regulates alternative splicing of EIF4G1 (affecting transcript variants encoding the N-terminus of EIF4G1) and of an AURKA 5'UTR-included exon; reporter constructs show this AURKA 5'UTR exon enhances expression, suggesting HNRNPH1 contributes to regulating AURKA protein levels. HNRNPH1 is identified as a MYCN transcriptional target in neuroblastoma.","method":"Short- and long-read RNA-seq after HNRNPH1 depletion, reporter constructs (5'UTR exon), ChIP/expression analysis for MYCN-HNRNPH1 axis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, reporter construct for AURKA 5'UTR function, transcriptome-wide splicing analysis, single lab, not yet peer-reviewed","pmids":["40766465"],"is_preprint":true},{"year":2024,"finding":"RNA G-quadruplexes mediate cooperative HNRNPH binding: rG4 unfolding by HNRNPH exposes multiple G-rich binding sites, establishing indirect cooperativity that is amplified to achieve switch-like splicing regulation of hundreds of exons; rG4-disrupting variants in tumors alter HNRNPH-dependent splicing patterns in breast cancer.","method":"High-throughput in vivo and in vitro binding studies, theoretical modeling of cooperativity, splice event analysis in tumor cohort data","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, multiple in vitro and in vivo assays with modeling, but not yet peer-reviewed; single lab","pmids":["41867855"],"is_preprint":true},{"year":2019,"finding":"LINC00162 interacts with HNRNPH1 and decreases splicing of the anti-apoptotic BCL-XL variant, increasing sensitivity of gastric cancer cells to 5-aza-dC; knockdown of LINC00162 decreases and overexpression increases 5-aza-dC sensitivity in vitro and in vivo.","method":"RNA immunoprecipitation (LINC00162-HNRNPH1 interaction), splicing analysis of BCL-XL, siRNA/overexpression, in vivo tumor model","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP for RNA-protein interaction, splicing assay, functional rescue, single lab, mechanistic role of HNRNPH1 in this axis not deeply resolved","pmids":["30914798"],"is_preprint":false},{"year":2025,"finding":"HNRNPH1 interacts with METTL14 to destabilize SPI1 mRNA via the lncRNA lnc-SPI1U; lnc-SPI1U binds HNRNPH1/F and destabilizes SPI1 mRNA, suppressing myeloid differentiation through a PU.1-dependent feedback loop.","method":"RNA immunoprecipitation (lnc-SPI1U-HNRNPH1/F), mRNA stability assay, siRNA knockdown/overexpression, ChIP for PU.1 binding","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP for RNA-protein interaction, functional assays, but role of HNRNPH1 specifically vs. HNRNPF not fully disambiguated, single lab","pmids":["41136556"],"is_preprint":false},{"year":2025,"finding":"HNRNPH1 MACC1 interaction (via MACC1 SH3 domain and HNRNPH1 GYR domain) promotes IRAK1-L long isoform production by preventing the short isoform; HNRNPH1 directly binds the pre-mRNA segment comprising IRAK1 exon 11, bridging MACC1's regulation of IRAK1 splicing in lung adenocarcinoma.","method":"Co-immunoprecipitation with domain mapping (SH3/GYR), RNA immunoprecipitation (HNRNPH1 binding to IRAK1 pre-mRNA), splicing analysis (minigene/RT-PCR), siRNA knockdown","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — domain-mapping Co-IP and RIP with functional splicing readout, single lab, moderately rigorous","pmids":["39221900"],"is_preprint":false}],"current_model":"HNRNPH1 is a nuclear RNA-binding protein that specifically recognizes G-rich RNA sequences—including RNA G-quadruplexes, which it destabilizes non-catalytically—to regulate alternative pre-mRNA splicing of hundreds of targets; it recruits splicing co-regulators (PTBP1, PTBP2, SRSF3), interacts with transcription factors (AR, NRF1) at gene promoters, undergoes PTK6-mediated Y210 phosphorylation and PRMT1-mediated arginine methylation that modulate its phase separation and RNA-binding activity, and plays essential roles in germ cell development, neuronal differentiation, mitochondrial homeostasis, and dopaminergic neurotransmission underlying addiction-related behaviors."},"narrative":{"mechanistic_narrative":"HNRNPH1 is a nuclear RNA-binding protein that recognizes G-rich RNA elements to act as a sequence-specific regulator of alternative pre-mRNA splicing across hundreds of targets [PMID:21915099, PMID:17567613, PMID:37248947]. Its splicing activity rests on a defined biochemical mechanism: through its qRRM1–qRRM2 domains it binds G-rich sequences with low-nanomolar affinity and non-catalytically destabilizes RNA G-quadruplex (G4) structures, driving the bound RNA toward a non-G4 state that licenses productive splicing decisions, as demonstrated for EWSR1 exon 8 in Ewing sarcoma [PMID:31511320, PMID:35639772]. Functionally, it dictates exon inclusion/exclusion outcomes in disease-relevant transcripts including MADD/IG20 and RON in glioblastoma [PMID:21915099], PLP/DM20 in oligodendrocytes [PMID:17567613], OPRM1 in human brain [PMID:25122903], and a cold-responsive RBM3 poison exon whose temperature-dependent skipping it controls via a thermosensitive G-rich interaction [PMID:37248947]. HNRNPH1 does not act alone but assembles position-dependent regulatory networks with co-regulators such as PTBP1, PTBP2, SRSF3 and BCAS2, sometimes cooperatively and sometimes competitively, to set splice-site choice [PMID:31391218, PMID:35739118, PMID:36499164, PMID:39520542]. A low-complexity LC1 domain drives reversible phase separation that is required for interaction with other RNA-binding proteins and for splicing activity, and this behavior is tuned by post-translational modification: PTK6 phosphorylates HNRNPH1 at Y210 to promote liquid-liquid phase separation and splicing switching, while PRMT1-mediated arginine methylation suppresses its mRNA binding [PMID:34873036, PMID:34027271, PMID:40103198]. Beyond splicing, HNRNPH1 participates in nuclear RNA surveillance through an RNA-independent association with the MTR4/MTREX helicase [PMID:34470577], engages transcription factors at gene promoters—AR in Sertoli cells and NRF1 at the DRP1 promoter during mitochondrial retrograde signaling [PMID:36718792, PMID:38898233]—and is essential for germ cell development, where its conditional loss causes aberrant meiotic splicing, blood-testis barrier disruption, and sterility [PMID:35739118, PMID:36718792]. In mice, frameshift and 5'UTR variants in Hnrnph1 reduce hnRNP H protein levels and methamphetamine sensitivity through mesolimbic dopaminergic signaling, establishing it as a quantitative trait gene [PMID:26658939, PMID:31704785, PMID:32401417], and HNRNPH1 can functionally substitute for its paralog HNRNPH2 [PMID:37463454].","teleology":[{"year":2007,"claim":"Established that hnRNPH directs 5' splice site selection by binding G-rich enhancer elements, defining its core activity as a sequence-specific splicing regulator.","evidence":"siRNA knockdown, G-rich element mutagenesis, and minigene assays on PLP/DM20 in oligodendrocytes","pmids":["17567613"],"confidence":"High","gaps":["Did not resolve structural basis of G-rich recognition","Synergy with hnRNPF mechanistically undefined"]},{"year":2011,"claim":"Showed hnRNPH-controlled splicing has direct phenotypic consequences in cancer, linking isoform choice to apoptosis and invasion.","evidence":"isoform-specific knockdown and reciprocal rescue of MADD and RON splicing in glioblastoma cells","pmids":["21915099"],"confidence":"High","gaps":["Binding sites on these targets not biophysically mapped","Whether effects generalize beyond GBM untested here"]},{"year":2014,"claim":"Demonstrated that a human SNP altering hnRNPH binding changes splicing in vivo, connecting the protein's G-rich recognition to genetic variation in human brain.","evidence":"EMSA, minigene, morpholino, and postmortem prefrontal cortex analysis of OPRM1 rs9479757","pmids":["25122903"],"confidence":"High","gaps":["Downstream behavioral/clinical consequence not established","Full set of brain targets unknown"]},{"year":2015,"claim":"Identified Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity, moving it from a molecular regulator to an organismal behavioral determinant.","evidence":"TALEN frameshift editing with Rufy1 negative control, congenic lines, and behavioral pharmacology in mice","pmids":["26658939"],"confidence":"High","gaps":["Splicing targets mediating dopaminergic effect not pinpointed","Causal molecular pathway from gene to behavior incomplete"]},{"year":2015,"claim":"Placed hnRNPH1 in transcription-factor complexes and androgen signaling, expanding its role beyond splicing into gene-expression control.","evidence":"Co-IP with AR and SRC-3, siRNA knockdown, and prostate tumorigenesis assays","pmids":["26553749"],"confidence":"Medium","gaps":["Direct vs indirect AR interaction not fully resolved","Mechanism of AR-V7 regulation unclear"]},{"year":2019,"claim":"Defined the cooperative and competitive logic of hnRNPH1 with other splicing factors, showing position-dependent regulation underlies its target outcomes.","evidence":"minigene, RNA pull-down/EMSA, and knockdown analyses of hnRNPH1/PTBP1 on TCF3 and family-member-specific control of EWSR1 exon 8","pmids":["31391218","31511320"],"confidence":"High","gaps":["Stoichiometry and spatial arrangement of factors on RNA unresolved","Genome-wide cooperativity not yet established"]},{"year":2019,"claim":"Linked Hnrnph1 dosage to dopamine release and synaptic mitochondrial protein changes, providing a neurochemical mechanism for the addiction phenotype.","evidence":"operant self-administration, microdialysis, and synaptosomal proteomics in Hnrnph1+/- mice","pmids":["31704785"],"confidence":"High","gaps":["How hnRNP H elevation alters mitochondrial proteins mechanistically unclear","Direct splicing targets in striatum unidentified"]},{"year":2021,"claim":"Identified phase separation of the LC1 domain as the structural basis for hnRNPH1 protein interactions and splicing activity.","evidence":"in vitro droplet assays, domain deletion constructs, and splicing/transcription reporters","pmids":["34873036"],"confidence":"Medium","gaps":["In vivo relevance of droplets vs polymers not resolved","Regulation of phase behavior by signals not addressed here"]},{"year":2021,"claim":"Extended hnRNPH1 into nuclear RNA surveillance and arginine-methylation control, broadening its mechanistic repertoire.","evidence":"RNA-independent Co-IP with MTR4/MTREX and NEAT1v2/IL8 assays; PRMT1 methylation MS and RIP with hepatocyte PRMT1-KO mice","pmids":["34470577","34027271"],"confidence":"Medium","gaps":["Whether MTR4 association is direct unknown","Methylated residues and their splicing impact not mapped"]},{"year":2022,"claim":"Established the biophysical mechanism of G-quadruplex destabilization and demonstrated an essential germ-cell developmental role with defined splicing co-regulators.","evidence":"biophysical binding/CD/NMR and domain deletions on EWSR1 G4; conditional Hnrnph1 KO with RNA-seq and Co-IP for PTBP2/SRSF3","pmids":["35639772","35739118"],"confidence":"High","gaps":["Generality of non-catalytic G4 destabilization across targets not proven","Sertoli vs germ-intrinsic contributions not separated here"]},{"year":2023,"claim":"Revealed hnRNPH1 as a thermosensor for RBM3 splicing and as a dual splicing/transcription regulator partnering AR at promoters in Sertoli cells.","evidence":"genome-wide CRISPR screen in iPSC-neurons with temperature shift for RBM3; conditional Sertoli KO with Co-IP (PTBP1, AR) and ChIP","pmids":["37248947","36718792"],"confidence":"High","gaps":["Molecular basis of thermosensitive binding unresolved","Direct vs cooperative promoter binding mechanism unclear"]},{"year":2023,"claim":"Showed HNRNPH1 can functionally compensate for its paralog HNRNPH2, clarifying paralog redundancy in disease models.","evidence":"Hnrnph2 knockin/knockout mouse models with Kapβ2 Co-IP and Hnrnph1 expression quantification","pmids":["37463454"],"confidence":"High","gaps":["Extent of overlapping vs distinct targets between paralogs not defined","Compensation mechanism at gene-regulatory level unknown"]},{"year":2024,"claim":"Connected PTK6 phosphorylation at Y210 to phase separation and a splicing-to-autophagy outcome, and identified hnRNPH1 as a mediator of mitochondrial retrograde signaling.","evidence":"Co-IP, Y210 mutagenesis, FRAP/LLPS, and NBR1 splicing in CRC; subcellular fractionation, NRF1 Co-IP, ChIP on DRP1 promoter and DRP1 Ser616 phosphorylation","pmids":["40103198","38898233"],"confidence":"Medium","gaps":["Direct kinase action vs scaffolding for DRP1 not fully separated","Link between LLPS state and DRP1 regulation untested"]},{"year":2024,"claim":"Defined hnRNPH1 as a host factor co-opted by multiple viruses through G4-driven cytoplasmic retention and direct protein interactions affecting innate immunity and viral replication.","evidence":"RNA pull-down, fractionation, IFN reporter, and Co-IP across yellow fever, JEV, and influenza A systems with RRM-domain mutagenesis","pmids":["39094585","39694377","39858792"],"confidence":"Medium","gaps":["Whether antiviral and proviral roles reflect distinct complexes unresolved","In vivo relevance of viral hijacking not established"]},{"year":null,"claim":"How HNRNPH1's modular activities—G4 destabilization, phase separation, post-translational tuning, and promoter-level transcription regulation—are integrated to select among hundreds of targets in a given cell state remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking PTM state to target selectivity","Structural basis of cooperativity across multiple G-runs not solved","Direct human disease causation by HNRNPH1 mutation not established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,6,14,16,26]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[17,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,22,23]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,23]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,6,13,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[17,22]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[13,17,28]}],"complexes":["hnRNPH1-MTR4/MTREX complex","BCAS2-hnRNPH1-SRSF3 splicing complex"],"partners":["PTBP1","PTBP2","SRSF3","AR","NRF1","MTREX","PTK6","BCAS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31943","full_name":"Heterogeneous nuclear ribonucleoprotein H","aliases":[],"length_aa":449,"mass_kda":49.2,"function":"This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Mediates pre-mRNA alternative splicing regulation. Inhibits, together with CUGBP1, insulin receptor (IR) pre-mRNA exon 11 inclusion in myoblast. Binds to the IR RNA. 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NONCODING RNA 672; LINC00672","url":"https://www.omim.org/entry/617544"},{"mim_id":"608449","title":"POLYPYRIMIDINE TRACT-BINDING PROTEIN 2; PTBP2","url":"https://www.omim.org/entry/608449"},{"mim_id":"604424","title":"HOMEODOMAIN-INTERACTING PROTEIN KINASE 3; HIPK3","url":"https://www.omim.org/entry/604424"},{"mim_id":"602792","title":"HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER D; HIST1H2AD","url":"https://www.omim.org/entry/602792"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39221900","citation_count":3,"is_preprint":false},{"pmid":"39520542","id":"PMC_39520542","title":"BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39520542","citation_count":2,"is_preprint":false},{"pmid":"40468317","id":"PMC_40468317","title":"HNRNPH1 promotes autophagy to inhibit the development of lung adenocarcinoma via the HSP90AB1/MAP1LC3B axis.","date":"2025","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/40468317","citation_count":2,"is_preprint":false},{"pmid":"41301529","id":"PMC_41301529","title":"Modulation of Spliceosomal Proteins hnRNPH1 and H2 Increases Melanoma Cell Pro-Inflammatory Signaling In Vitro.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41301529","citation_count":1,"is_preprint":false},{"pmid":"41136556","id":"PMC_41136556","title":"Super-enhancer-associated long noncoding RNA lnc-SPI1U mediates SPI1 feedback regulation by interacting with HNRNPH1 and HNRNPF.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41136556","citation_count":0,"is_preprint":false},{"pmid":"41867855","id":"PMC_41867855","title":"RNA G-quadruplexes mediate cooperativity in HNRNPH binding and splicing regulation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41867855","citation_count":0,"is_preprint":false},{"pmid":"40766465","id":"PMC_40766465","title":"HNRNPH1-mediated splicing events regulate EIF4G1 transcript variant composition and the organization of the AURKA 5'UTR.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40766465","citation_count":0,"is_preprint":false},{"pmid":"41872153","id":"PMC_41872153","title":"HNRNPH1 drives glioblastoma progression by regulating the splicing of cell cycle genes.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41872153","citation_count":0,"is_preprint":false},{"pmid":"40159973","id":"PMC_40159973","title":"[The splicing factor HNRNPH1 regulates Circ-MYOCD back-splicing to modulate the course of cardiac hypertrophy].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/40159973","citation_count":0,"is_preprint":false},{"pmid":"37400142","id":"PMC_37400142","title":"Acute Undifferentiated Leukemia With a Balanced t(5;10)(q35;p12) Resulting in Fusion of HNRNPH1 With MLLT10.","date":"2023","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37400142","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.04.686541","title":"Preclinical evaluation of antisense oligonucleotide therapy in a mouse model of  <i>HNRNPH2</i>  -related neurodevelopmental disorder","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.686541","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.28.667222","title":"HNRNPH1-mediated splicing events regulate  <i>EIF4G1</i>  transcript variant composition and the organization of the  <i>AURKA</i>  5’UTR","date":"2025-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.28.667222","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.05.668798","title":"Time-Resolved Transcriptomics Reveal Spliceosomal Disruption and Senescence Pathways in Crocin-Treated Hepatocellular Carcinoma Cells","date":"2025-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.668798","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.01.657310","title":"Multimodal Validation of the Existence of Transitional Cerebellar Progenitors in the Human Fetal Cerebellum","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.01.657310","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.21.24312358","title":"aiHumanoid Simulations Uncover Dominant-Negative Effects in HNRNPH2-Related Neurodevelopmental Disorders","date":"2024-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.21.24312358","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.12.687994","title":"Phase Behavior of TDP-43 and hnRNPH1: From Soluble and Aggregated States to Liquid-Like Droplets","date":"2025-11-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.12.687994","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.27.690981","title":"Mechanistic analysis of compounds that modulate VEGF-A splicing in podocytes with therapeutic potential for diabetic nephropathy","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.27.690981","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35067,"output_tokens":9456,"usd":0.123521,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19544,"output_tokens":4746,"usd":0.108185,"stage2_stop_reason":"end_turn"},"total_usd":0.231706,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPH controls alternative splicing of IG20/MADD (exon 16) and RON (exon 11) pre-mRNAs in glioblastoma, shifting splicing toward anti-apoptotic and pro-invasive isoforms; ablation of hnRNPH increases cell death and reduces invasiveness, phenotypes rescued by isoform-specific knockdown of the respective variants.\",\n      \"method\": \"siRNA knockdown, isoform-specific knockdown, splicing redirection, minigene assays in GBM cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional rescue experiments with two independent splicing targets, replicated across GBM specimens and cell lines\",\n      \"pmids\": [\"21915099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"hnRNPH binds G-rich enhancer sequences (M2) in PLP exon 3B and an intronic splicing enhancer (ISE) to promote DM20 5' splice site selection; knockdown of hnRNPH increases the PLP/DM20 ratio in oligodendrocytes, and combined knockdown of hnRNPH and hnRNPF has a synergistic effect mediated through the M2 element.\",\n      \"method\": \"siRNA knockdown in differentiated oligodendrocytes, mutagenesis of G-rich elements, minigene splicing assays, protein binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of binding sites combined with functional knockdown and multiple orthogonal assays\",\n      \"pmids\": [\"17567613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPH binds G-rich sequences at the OPRM1 intronic SNP site (rs9479757); the G-to-A SNP transition weakens hnRNPH binding and causes exon 2 skipping, altering OPRM1 splice-variant mRNA and hMOR-1 protein levels in vitro and in human postmortem prefrontal cortex.\",\n      \"method\": \"EMSA (electrophoretic mobility shift assay), minigene splicing assay, siRNA knockdown, antisense morpholino oligonucleotide studies, human postmortem brain analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding demonstrated by EMSA, functional splicing confirmed by minigene and morpholino, validated in human tissue\",\n      \"pmids\": [\"25122903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPH1 physically interacts with androgen receptor (AR) and steroid receptor coactivator-3 (SRC-3), and regulates expression of AR and its splice variant AR-V7; siRNA silencing of hnRNPH1 reduces AR and AR-V7 expression and sensitizes prostate cancer cells to bicalutamide.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ectopic expression of miR-212 mimics, in vivo prostate tumorigenesis assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for protein interactions, functional rescue experiments, single lab with multiple methods\",\n      \"pmids\": [\"26553749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TALEN-mediated frameshift deletions in the first coding exon of Hnrnph1 (but not the neighboring gene Rufy1) recapitulate reduced methamphetamine-induced locomotor activity in mice, establishing Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity with a mechanism involving mesolimbic dopaminergic neurotransmission.\",\n      \"method\": \"TALEN gene editing, interval-specific congenic mouse lines, transcriptome analysis (mRNA-seq), behavioral pharmacology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning confirmed by gene editing with negative control (Rufy1), replicated across congenic lines with transcriptomic mechanistic follow-up\",\n      \"pmids\": [\"26658939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HNRNPH1 (and H2) bind exon 7 of Trf2 pre-mRNA and prevent production of the short TRF2-S isoform; HNRNPH silencing selectively elevates TRF2-S levels during neuronal differentiation, and CRISPR/Cas9-mediated deletion of hnRNPH2 accelerates NGF-triggered neuronal differentiation.\",\n      \"method\": \"Affinity pull-down, siRNA silencing, CRISPR/Cas9 deletion, isoform-specific RT-PCR, NGF differentiation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity pull-down identifies binding, functional silencing and CRISPR deletion with isoform phenotype, single lab\",\n      \"pmids\": [\"27117401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HNRNPH1 (but not other homologous family members) facilitates exclusion of EWSR1 exon 8 from EWS-FLI1 pre-mRNA in Ewing sarcoma cells; this recruitment is driven by guanine-rich sequences within EWSR1 exon 8 capable of folding into RNA G-quadruplex structures, and an RNA G-quadruplex mimetic modulates HNRNPH1 binding and reduces growth of fusion-positive cells.\",\n      \"method\": \"Minigene splicing assay, siRNA knockdown, RNA pull-down, G-quadruplex RNA mimetic binding assay, cell growth assays, pyridostatin treatment\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding and functional specificity demonstrated with multiple orthogonal methods, mechanistic link between G4 sequences and HNRNPH1-dependent splicing\",\n      \"pmids\": [\"31511320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hnrnph1 heterozygous mutant mice show reduced methamphetamine reinforcement and intake, reduced methamphetamine-induced dopamine release in the nucleus accumbens, and a twofold increase in hnRNP H protein in striatal synaptosomes; synaptosomal proteomics revealed increased baseline mitochondrial complex I and V proteins in H1+/- mice that dynamically changed with methamphetamine administration.\",\n      \"method\": \"Operant self-administration, conditioned place preference, in vivo microdialysis, immunohistochemistry, immunoblot, synaptosomal proteomics (mass spectrometry)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal behavioral and neurochemical methods, protein-level mechanistic follow-up via proteomics, single lab but very comprehensive\",\n      \"pmids\": [\"31704785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPH1 and PTBP1 cooperatively regulate TCF3 mutually exclusive alternative splicing: hnRNPH1 binds exonic splicing silencers (ESSs) in exon 18b while PTBP1 binds conserved intronic splicing silencers (ISSs) between the two mutually exclusive exons; position-dependent interactions between these factors are essential for proper MEAS.\",\n      \"method\": \"Minigene splicing assay, siRNA knockdown, RNA pull-down/EMSA for factor binding to ISSs and ESSs\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional binding and splicing assays with mutagenesis of binding sites, single lab\",\n      \"pmids\": [\"31391218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNPH1/H2 proteins bind a conserved G-rich sequence element within the U11-48K pre-mRNA and counteract activation of an alternative 3' splice site by U11 snRNP; knockdown of hnRNPH1/H2 or mutation of the G-run enhances 3' splice site activation, revealing a regulatory interplay between hnRNPH1/H2, U1 snRNP, and U11 snRNP.\",\n      \"method\": \"In vitro binding assays, siRNA knockdown, minigene splicing analysis, phylogenetic conservation analysis, mutation of G-run elements\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with functional knockdown and mutagenesis, single lab\",\n      \"pmids\": [\"23335637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The LC1 low-complexity domain of hnRNPH1 undergoes reversible phase separation into polymers or liquid-like droplets, which is critical for interaction with other RNA-binding proteins and for alternative splicing activity; the LC2 domain does not contribute to phase separation but contributes to transcriptional activation when fused to a DNA-binding domain.\",\n      \"method\": \"Phase separation assays (in vitro droplet formation), domain deletion/mutation constructs, splicing reporter assays, transcriptional activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phase separation with functional splicing and transcription assays, single lab with domain-specific dissection\",\n      \"pmids\": [\"34873036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPH1 binds the mRNA of PTPN6 and negatively regulates its expression; hnRNPH1 knockdown in CML cells increases PTPN6 levels, thereby suppressing PI3K/AKT activation and inhibiting cell proliferation while promoting apoptosis.\",\n      \"method\": \"RNA immunoprecipitation/pulldown, siRNA knockdown, western blot, in vitro and in vivo CML cell models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-binding shown by pulldown/RIP, functional pathway placement via knockdown and rescue, single lab\",\n      \"pmids\": [\"34295818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPH1 associates with the RNA helicase MTR4/MTREX in an RNA-independent manner and localizes in nuclear speckles; depletion of hnRNPH1 enhances NEAT1v2 stability and promotes NEAT1v2-mediated IL8 mRNA expression, indicating hnRNPH1-MTR4 complex mediates NEAT1v2 degradation to control IL8.\",\n      \"method\": \"Co-immunoprecipitation (RNA-independent), RNA stability assays, siRNA knockdown, nuclear localization (imaging), IL8 mRNA measurement\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA-independent Co-IP establishes protein complex, functional knockdown with mechanistic pathway, single lab\",\n      \"pmids\": [\"34470577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPH1 recruits PTBP2 and SRSF3 to modulate alternative splicing in germ cells; conditional knockout of Hnrnph1 in spermatogenic cells causes aberrant splicing of meiosis- and germ-Sertoli communication-related genes, asynapsis of chromosomes, and male and female sterility.\",\n      \"method\": \"Conditional knockout mice, RNA-seq splicing analysis, Co-immunoprecipitation for PTBP2/SRSF3 interaction, histology, fertility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with transcriptome-wide splicing analysis and Co-IP for complex, replicated across male and female germ cell contexts\",\n      \"pmids\": [\"35739118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HNRNPH1 binds EWSR1-exon 8 G-rich sequences with low nM affinity and destabilizes G-quadruplex (G4) structures formed by these sequences in a non-catalytic fashion, primarily through its qRRM1-qRRM2 domains; HNRNPH1 associates and dissociates faster from G4-folded RNA than from the same sequences in a non-G4 state, and binding favors accumulation of RNA in a non-G4 state to facilitate splicing regulation.\",\n      \"method\": \"Gel shift assays, spectroscopic assays (CD, NMR-related), biophysical binding measurements, domain-deletion constructs, minigene splicing, long-read sequencing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with biophysical assays, mutagenesis (domain deletions), multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"35639772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF3 and HNRNPH1 competitively bind to PRMT5 pre-mRNA at the region around the 3' splice site on intron 2 and the alternative 3' splice site on exon 4; IR-induced SRSF3 downregulation shifts the competitive balance toward HNRNPH1, increasing the PRMT5-ISO5 isoform level and enhancing tumor radiosensitivity.\",\n      \"method\": \"siRNA silencing of SRSF3 and HNRNPH1, RNA immunoprecipitation, minigene assays, in vivo xenograft irradiation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP demonstrates competitive binding, functional splicing changes with siRNA, in vivo validation, single lab\",\n      \"pmids\": [\"36499164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNRNPH1 mediates cold-dependent skipping of a poison exon in RBM3 pre-mRNA via a thermosensitive interaction with a G-rich motif within the poison exon; moderate hypothermia represses poison exon inclusion in an HNRNPH1-dependent manner, preventing NMD of RBM3 mRNA and enhancing RBM3 protein expression.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen in iPSC-derived neurons with RBM3 reporter, splicing analysis, HNRNPH1 knockdown, temperature-shift experiments, minigene assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — unbiased genome-wide screen identified HNRNPH1, mechanistic follow-up with minigene and thermosensitive binding, multiple orthogonal methods\",\n      \"pmids\": [\"37248947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNPH1 in Sertoli cells interacts with PTBP1 to regulate alternative splicing of target genes related to cell adhesion, and cooperates with androgen receptor (AR) to directly bind promoters of cell-cell junction and EGFR pathway genes and modulate their transcription; conditional knockout of hnRNPH1 in Sertoli cells disrupts blood-testis barrier, causes meiotic delay, germ cell apoptosis, and infertility.\",\n      \"method\": \"Conditional knockout mice (Sertoli cell-specific), Co-immunoprecipitation (hnRNPH1-PTBP1, hnRNPH1-AR), ChIP (promoter binding), RNA-seq, histology, fertility assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined phenotype, reciprocal Co-IP for protein partners, ChIP for direct promoter binding, multiple orthogonal methods\",\n      \"pmids\": [\"36718792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Murine knockin models of Hnrnph2 NLS mutations show that these mutations reduce interaction with the nuclear transport receptor Kapβ2 and cause cytoplasmic accumulation of hnRNPH2; Hnrnph2 knockout mice upregulate Hnrnph1 (genetic compensation), whereas knockin mice fail to upregulate Hnrnph1, establishing that HNRNPH1 can functionally substitute for HNRNPH2.\",\n      \"method\": \"Knockin and knockout mouse models, Co-IP for Kapβ2 interaction, immunofluorescence for localization, mRNA/protein quantification, behavioral phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple engineered mouse models with mechanistic biochemistry (Co-IP, localization), single lab but comprehensive genetic and molecular evidence\",\n      \"pmids\": [\"37463454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPH1 physically interacts with the mature hepatitis C virus core protein (HCVc174); this interaction was confirmed by pull-down and confocal imaging, and colocalization shifts from cytoplasm+nucleus to cytoplasm only in cells with replicating HCV, indicating active viral replication confines this interaction to the cytoplasm.\",\n      \"method\": \"Affinity purification with LC-MS/MS proteomics, pull-down confirmation, confocal colocalization imaging\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pull-down and imaging confirm interaction, localization shift is functionally described, but mechanism of functional consequence not deeply resolved\",\n      \"pmids\": [\"21823664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT1-mediated arginine methylation of hnRNP H1 suppresses its binding to mRNAs of complement pathway components including C3; PRMT1-dependent methylation requires phosphorylation and reduces complement component expression in vitro; hepatocyte-specific PRMT1 knockout increases complement expression and systemic inflammation in alcohol-fed mice.\",\n      \"method\": \"Mass spectrometry for arginine methylation, RNA immunoprecipitation for mRNA binding, hepatocyte-specific PRMT1 knockout mice, in vitro expression assays\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified PTM, RIP for binding, KO mice with defined pathway phenotype, single lab\",\n      \"pmids\": [\"34027271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTK6 physically interacts with HNRNPH1 and phosphorylates it at tyrosine Y210, promoting HNRNPH1 liquid-liquid phase separation (LLPS); LLPS of HNRNPH1 triggers splicing-switching of NBR1 exon 10 inclusion, thereby activating autophagy and suppressing apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, phospho-site mutagenesis (Y210), FRAP, LLPS assays (liquid droplet imaging), minigene/splicing analysis, in vitro kinase assay, PDO and CDX models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct phosphorylation by kinase with site-specific mutagenesis, FRAP for LLPS, functional splicing outcome linked to autophagy, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40103198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPH1 functions as a pivotal mediator of mitochondrial retrograde signaling: under mitochondrial stress, hnRNPH1 accumulates in the nucleus via AMPK-dependent mechanism, interacts with transcription factor NRF1, and binds the DRP1 promoter to enhance DRP1 transcription; in the cytoplasm, hnRNPH1 directly interacts with DRP1 and enhances DRP1 Ser616 phosphorylation, triggering DRP1 translocation to mitochondria and mitochondrial fission.\",\n      \"method\": \"Subcellular fractionation, Co-immunoprecipitation, ChIP (DRP1 promoter binding), AMPK inhibition, phospho-specific western blot, mitochondrial morphology imaging\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and fractionation with functional consequence, single lab with multiple methods\",\n      \"pmids\": [\"38898233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A conserved G-quadruplex within the polymerase coding region of yellow fever virus (orthoflavivirus) promotes viral replication and suppresses host stress responses via interactions with hnRNPH1; G4 binding to hnRNPH1 causes its cytoplasmic retention, impairing hnRNPH1 control of G4-containing tRNA fragments (tiRNAs) involved in stress-mediated translational reduction, thereby suppressing integrated stress responses and antiviral effects.\",\n      \"method\": \"Yellow fever virus infection, G4 identification, RNA pull-down for hnRNPH1 binding, subcellular fractionation (nuclear vs cytoplasmic localization), stress response assays, tiRNA analysis\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct G4-hnRNPH1 binding with functional localization change and defined pathway, single lab\",\n      \"pmids\": [\"39094585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPH1 stabilizes FLOT2 mRNA in an m6A-dependent manner: HNRNPH1 interacts with METTL14 to prevent its STUB1-mediated degradation, leading to increased m6A modification on FLOT2 mRNA; IGF2BP3 then recognizes the m6A modification and further stabilizes FLOT2 mRNA. HNRNPH1 knockdown reduces FLOT2 expression and NPC cell proliferation/invasion.\",\n      \"method\": \"Co-immunoprecipitation (HNRNPH1-METTL14), RNA stability assays, m6A quantification, siRNA knockdown, rescue experiments with METTL14 re-expression, in vitro and in vivo NPC models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, m6A assays, and functional rescue with defined pathway, single lab\",\n      \"pmids\": [\"39570559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JEV nonstructural protein NS3 captures HNRNPH1 to recruit poly A-binding protein cytoplasmic 1 (PABPC1) and eukaryotic translation initiation factor 4F (eIF4F) complex, promoting viral replication; HNRNPH1 normally inhibits RIG-I/MDA5 signaling to decrease interferon expression, and SOX10 downregulates HNRNPH1 during JEV infection.\",\n      \"method\": \"Co-immunoprecipitation (NS3-HNRNPH1, HNRNPH1-PABPC1, HNRNPH1-eIF4F), siRNA knockdown, overexpression, IFN reporter assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP establishes interactions, functional knockdown/overexpression with defined viral and innate immune phenotypes, single lab\",\n      \"pmids\": [\"39694377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPH1 suppresses influenza A virus (IAV) H1N1 and H9N2 replication by binding viral RNA of PB1, PA, and NP genes through its RRM1 and RRM2 domains and restraining viral polymerase activity; mutation of key tryptophan and tyrosine residues in RRM1 and RRM2 abolishes viral RNA binding and loss of polymerase suppression.\",\n      \"method\": \"Knockdown and overexpression in 293T cells, viral RNA binding assay, polymerase activity assay, site-directed mutagenesis of RRM domains\",\n      \"journal\": \"Microorganisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct RNA binding with active-site mutagenesis and functional polymerase assay, single lab\",\n      \"pmids\": [\"39858792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH1 interacts with IAV NS1 protein via the RBD domain of NS1 and the RRM and NLS regions of hnRNPH1; this interaction changes intracellular localization and splicing function of NS1, and HNRNPH1 interacts with p53 to regulate apoptosis; overexpression of hnRNPH1 decreases IAV multiplication while knockdown enhances replication.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments (truncation mutants), subcellular localization assay, splicing assay, apoptosis assay, overexpression/knockdown\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping, functional localization changes, multiple downstream assays, single lab\",\n      \"pmids\": [\"40052960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCAS2, hnRNPH1, and SRSF3 interact to form a complex that orchestrates alternative splicing of Trp53bp1 (53BP1), regulating DNA double-strand break repair during meiotic prophase I; conditional knockout of Bcas2 in germ cells impairs DSB repair and synapsis, and CLIP-seq mapped BCAS2 binding to 5' splice sites and GA-rich regions.\",\n      \"method\": \"Conditional knockout mice, CLIP-seq, Co-immunoprecipitation (BCAS2-hnRNPH1-SRSF3), splicing analysis, DSB repair assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq and Co-IP establish complex and binding sites, functional KO with defined meiotic phenotype, single lab\",\n      \"pmids\": [\"39520542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Four 5' UTR variants in the DBA/2J allele of Hnrnph1 collectively reduce reporter expression in HEK293 and N2a cells and correspond to decreased 5' UTR usage and reduced hnRNP H protein levels in 114 kb congenic mice striatum, identifying these 5' UTR variants as quantitative trait variants (QTVs) underlying molecular regulation of Hnrnph1.\",\n      \"method\": \"Molecular cloning and reporter assay (5' UTR variants), exon-level transcriptome analysis, immunoblot, congenic mouse lines\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reporter assay for 5' UTR function, protein-level confirmation in vivo, single lab with multiple complementary approaches\",\n      \"pmids\": [\"32401417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BL-associated TCF3 mutations reduce binding of hnRNPH1 to exon 18b ESS sequences, causing greater exon 18b inclusion and generating more of the mutated E47 isoform; upregulation of E47 dysregulates TCF3 targets PTPN6 and CCND3 involved in BL pathogenesis.\",\n      \"method\": \"RNA pull-down/EMSA (hnRNPH1 binding to WT vs. mutant exon 18b), minigene splicing assays, siRNA knockdown, qRT-PCR for TCF3 targets\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with mutant sequences, functional splicing assays, pathway-level follow-up, single lab\",\n      \"pmids\": [\"32449435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH1 regulates alternative splicing of EIF4G1 (affecting transcript variants encoding the N-terminus of EIF4G1) and of an AURKA 5'UTR-included exon; reporter constructs show this AURKA 5'UTR exon enhances expression, suggesting HNRNPH1 contributes to regulating AURKA protein levels. HNRNPH1 is identified as a MYCN transcriptional target in neuroblastoma.\",\n      \"method\": \"Short- and long-read RNA-seq after HNRNPH1 depletion, reporter constructs (5'UTR exon), ChIP/expression analysis for MYCN-HNRNPH1 axis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, reporter construct for AURKA 5'UTR function, transcriptome-wide splicing analysis, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"40766465\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNA G-quadruplexes mediate cooperative HNRNPH binding: rG4 unfolding by HNRNPH exposes multiple G-rich binding sites, establishing indirect cooperativity that is amplified to achieve switch-like splicing regulation of hundreds of exons; rG4-disrupting variants in tumors alter HNRNPH-dependent splicing patterns in breast cancer.\",\n      \"method\": \"High-throughput in vivo and in vitro binding studies, theoretical modeling of cooperativity, splice event analysis in tumor cohort data\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, multiple in vitro and in vivo assays with modeling, but not yet peer-reviewed; single lab\",\n      \"pmids\": [\"41867855\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LINC00162 interacts with HNRNPH1 and decreases splicing of the anti-apoptotic BCL-XL variant, increasing sensitivity of gastric cancer cells to 5-aza-dC; knockdown of LINC00162 decreases and overexpression increases 5-aza-dC sensitivity in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation (LINC00162-HNRNPH1 interaction), splicing analysis of BCL-XL, siRNA/overexpression, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP for RNA-protein interaction, splicing assay, functional rescue, single lab, mechanistic role of HNRNPH1 in this axis not deeply resolved\",\n      \"pmids\": [\"30914798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH1 interacts with METTL14 to destabilize SPI1 mRNA via the lncRNA lnc-SPI1U; lnc-SPI1U binds HNRNPH1/F and destabilizes SPI1 mRNA, suppressing myeloid differentiation through a PU.1-dependent feedback loop.\",\n      \"method\": \"RNA immunoprecipitation (lnc-SPI1U-HNRNPH1/F), mRNA stability assay, siRNA knockdown/overexpression, ChIP for PU.1 binding\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP for RNA-protein interaction, functional assays, but role of HNRNPH1 specifically vs. HNRNPF not fully disambiguated, single lab\",\n      \"pmids\": [\"41136556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH1 MACC1 interaction (via MACC1 SH3 domain and HNRNPH1 GYR domain) promotes IRAK1-L long isoform production by preventing the short isoform; HNRNPH1 directly binds the pre-mRNA segment comprising IRAK1 exon 11, bridging MACC1's regulation of IRAK1 splicing in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping (SH3/GYR), RNA immunoprecipitation (HNRNPH1 binding to IRAK1 pre-mRNA), splicing analysis (minigene/RT-PCR), siRNA knockdown\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — domain-mapping Co-IP and RIP with functional splicing readout, single lab, moderately rigorous\",\n      \"pmids\": [\"39221900\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPH1 is a nuclear RNA-binding protein that specifically recognizes G-rich RNA sequences—including RNA G-quadruplexes, which it destabilizes non-catalytically—to regulate alternative pre-mRNA splicing of hundreds of targets; it recruits splicing co-regulators (PTBP1, PTBP2, SRSF3), interacts with transcription factors (AR, NRF1) at gene promoters, undergoes PTK6-mediated Y210 phosphorylation and PRMT1-mediated arginine methylation that modulate its phase separation and RNA-binding activity, and plays essential roles in germ cell development, neuronal differentiation, mitochondrial homeostasis, and dopaminergic neurotransmission underlying addiction-related behaviors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPH1 is a nuclear RNA-binding protein that recognizes G-rich RNA elements to act as a sequence-specific regulator of alternative pre-mRNA splicing across hundreds of targets [#0, #1, #16]. Its splicing activity rests on a defined biochemical mechanism: through its qRRM1\\u2013qRRM2 domains it binds G-rich sequences with low-nanomolar affinity and non-catalytically destabilizes RNA G-quadruplex (G4) structures, driving the bound RNA toward a non-G4 state that licenses productive splicing decisions, as demonstrated for EWSR1 exon 8 in Ewing sarcoma [#6, #14]. Functionally, it dictates exon inclusion/exclusion outcomes in disease-relevant transcripts including MADD/IG20 and RON in glioblastoma [#0], PLP/DM20 in oligodendrocytes [#1], OPRM1 in human brain [#2], and a cold-responsive RBM3 poison exon whose temperature-dependent skipping it controls via a thermosensitive G-rich interaction [#16]. HNRNPH1 does not act alone but assembles position-dependent regulatory networks with co-regulators such as PTBP1, PTBP2, SRSF3 and BCAS2, sometimes cooperatively and sometimes competitively, to set splice-site choice [#8, #13, #15, #28]. A low-complexity LC1 domain drives reversible phase separation that is required for interaction with other RNA-binding proteins and for splicing activity, and this behavior is tuned by post-translational modification: PTK6 phosphorylates HNRNPH1 at Y210 to promote liquid-liquid phase separation and splicing switching, while PRMT1-mediated arginine methylation suppresses its mRNA binding [#10, #20, #21]. Beyond splicing, HNRNPH1 participates in nuclear RNA surveillance through an RNA-independent association with the MTR4/MTREX helicase [#12], engages transcription factors at gene promoters\\u2014AR in Sertoli cells and NRF1 at the DRP1 promoter during mitochondrial retrograde signaling [#17, #22]\\u2014and is essential for germ cell development, where its conditional loss causes aberrant meiotic splicing, blood-testis barrier disruption, and sterility [#13, #17]. In mice, frameshift and 5'UTR variants in Hnrnph1 reduce hnRNP H protein levels and methamphetamine sensitivity through mesolimbic dopaminergic signaling, establishing it as a quantitative trait gene [#4, #7, #29], and HNRNPH1 can functionally substitute for its paralog HNRNPH2 [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that hnRNPH directs 5' splice site selection by binding G-rich enhancer elements, defining its core activity as a sequence-specific splicing regulator.\",\n      \"evidence\": \"siRNA knockdown, G-rich element mutagenesis, and minigene assays on PLP/DM20 in oligodendrocytes\",\n      \"pmids\": [\"17567613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve structural basis of G-rich recognition\", \"Synergy with hnRNPF mechanistically undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed hnRNPH-controlled splicing has direct phenotypic consequences in cancer, linking isoform choice to apoptosis and invasion.\",\n      \"evidence\": \"isoform-specific knockdown and reciprocal rescue of MADD and RON splicing in glioblastoma cells\",\n      \"pmids\": [\"21915099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding sites on these targets not biophysically mapped\", \"Whether effects generalize beyond GBM untested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that a human SNP altering hnRNPH binding changes splicing in vivo, connecting the protein's G-rich recognition to genetic variation in human brain.\",\n      \"evidence\": \"EMSA, minigene, morpholino, and postmortem prefrontal cortex analysis of OPRM1 rs9479757\",\n      \"pmids\": [\"25122903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream behavioral/clinical consequence not established\", \"Full set of brain targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity, moving it from a molecular regulator to an organismal behavioral determinant.\",\n      \"evidence\": \"TALEN frameshift editing with Rufy1 negative control, congenic lines, and behavioral pharmacology in mice\",\n      \"pmids\": [\"26658939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing targets mediating dopaminergic effect not pinpointed\", \"Causal molecular pathway from gene to behavior incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed hnRNPH1 in transcription-factor complexes and androgen signaling, expanding its role beyond splicing into gene-expression control.\",\n      \"evidence\": \"Co-IP with AR and SRC-3, siRNA knockdown, and prostate tumorigenesis assays\",\n      \"pmids\": [\"26553749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect AR interaction not fully resolved\", \"Mechanism of AR-V7 regulation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the cooperative and competitive logic of hnRNPH1 with other splicing factors, showing position-dependent regulation underlies its target outcomes.\",\n      \"evidence\": \"minigene, RNA pull-down/EMSA, and knockdown analyses of hnRNPH1/PTBP1 on TCF3 and family-member-specific control of EWSR1 exon 8\",\n      \"pmids\": [\"31391218\", \"31511320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and spatial arrangement of factors on RNA unresolved\", \"Genome-wide cooperativity not yet established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked Hnrnph1 dosage to dopamine release and synaptic mitochondrial protein changes, providing a neurochemical mechanism for the addiction phenotype.\",\n      \"evidence\": \"operant self-administration, microdialysis, and synaptosomal proteomics in Hnrnph1+/- mice\",\n      \"pmids\": [\"31704785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How hnRNP H elevation alters mitochondrial proteins mechanistically unclear\", \"Direct splicing targets in striatum unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified phase separation of the LC1 domain as the structural basis for hnRNPH1 protein interactions and splicing activity.\",\n      \"evidence\": \"in vitro droplet assays, domain deletion constructs, and splicing/transcription reporters\",\n      \"pmids\": [\"34873036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of droplets vs polymers not resolved\", \"Regulation of phase behavior by signals not addressed here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended hnRNPH1 into nuclear RNA surveillance and arginine-methylation control, broadening its mechanistic repertoire.\",\n      \"evidence\": \"RNA-independent Co-IP with MTR4/MTREX and NEAT1v2/IL8 assays; PRMT1 methylation MS and RIP with hepatocyte PRMT1-KO mice\",\n      \"pmids\": [\"34470577\", \"34027271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MTR4 association is direct unknown\", \"Methylated residues and their splicing impact not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the biophysical mechanism of G-quadruplex destabilization and demonstrated an essential germ-cell developmental role with defined splicing co-regulators.\",\n      \"evidence\": \"biophysical binding/CD/NMR and domain deletions on EWSR1 G4; conditional Hnrnph1 KO with RNA-seq and Co-IP for PTBP2/SRSF3\",\n      \"pmids\": [\"35639772\", \"35739118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of non-catalytic G4 destabilization across targets not proven\", \"Sertoli vs germ-intrinsic contributions not separated here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed hnRNPH1 as a thermosensor for RBM3 splicing and as a dual splicing/transcription regulator partnering AR at promoters in Sertoli cells.\",\n      \"evidence\": \"genome-wide CRISPR screen in iPSC-neurons with temperature shift for RBM3; conditional Sertoli KO with Co-IP (PTBP1, AR) and ChIP\",\n      \"pmids\": [\"37248947\", \"36718792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of thermosensitive binding unresolved\", \"Direct vs cooperative promoter binding mechanism unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed HNRNPH1 can functionally compensate for its paralog HNRNPH2, clarifying paralog redundancy in disease models.\",\n      \"evidence\": \"Hnrnph2 knockin/knockout mouse models with Kapβ2 Co-IP and Hnrnph1 expression quantification\",\n      \"pmids\": [\"37463454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent of overlapping vs distinct targets between paralogs not defined\", \"Compensation mechanism at gene-regulatory level unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PTK6 phosphorylation at Y210 to phase separation and a splicing-to-autophagy outcome, and identified hnRNPH1 as a mediator of mitochondrial retrograde signaling.\",\n      \"evidence\": \"Co-IP, Y210 mutagenesis, FRAP/LLPS, and NBR1 splicing in CRC; subcellular fractionation, NRF1 Co-IP, ChIP on DRP1 promoter and DRP1 Ser616 phosphorylation\",\n      \"pmids\": [\"40103198\", \"38898233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase action vs scaffolding for DRP1 not fully separated\", \"Link between LLPS state and DRP1 regulation untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined hnRNPH1 as a host factor co-opted by multiple viruses through G4-driven cytoplasmic retention and direct protein interactions affecting innate immunity and viral replication.\",\n      \"evidence\": \"RNA pull-down, fractionation, IFN reporter, and Co-IP across yellow fever, JEV, and influenza A systems with RRM-domain mutagenesis\",\n      \"pmids\": [\"39094585\", \"39694377\", \"39858792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether antiviral and proviral roles reflect distinct complexes unresolved\", \"In vivo relevance of viral hijacking not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPH1's modular activities\\u2014G4 destabilization, phase separation, post-translational tuning, and promoter-level transcription regulation\\u2014are integrated to select among hundreds of targets in a given cell state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking PTM state to target selectivity\", \"Structural basis of cooperativity across multiple G-runs not solved\", \"Direct human disease causation by HNRNPH1 mutation not established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 6, 14, 16, 26]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [17, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 22, 23]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 6, 13, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [17, 22]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [13, 17, 28]}\n    ],\n    \"complexes\": [\n      \"hnRNPH1-MTR4/MTREX complex\",\n      \"BCAS2-hnRNPH1-SRSF3 splicing complex\"\n    ],\n    \"partners\": [\n      \"PTBP1\",\n      \"PTBP2\",\n      \"SRSF3\",\n      \"AR\",\n      \"NRF1\",\n      \"MTREX\",\n      \"PTK6\",\n      \"BCAS2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}