{"gene":"HDGFL2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2012,"finding":"HRP-2 (HDGFL2) contains an integrase-binding domain (IBD) identical to that of LEDGF/p75 and can bind HIV-1 integrase (IN), stimulating its integration activity; in LEDGF/p75 knockout cells, HRP-2 mediates residual HIV-1 replication and partially compensates for LEDGF/p75 loss in tethering the pre-integration complex to chromatin.","method":"Human somatic LEDGF/p75 knockout cell line (homologous recombination), spreading HIV-1 infection assay, siRNA knockdown of HRP-2, LEDIN inhibitor competition assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic KO and KD experiments in human cells with direct functional HIV replication and integration readouts, replicated across multiple labs (PMIDs 22396646, 23042676, 23046603)","pmids":["22396646"],"is_preprint":false},{"year":2005,"finding":"HRP-2 (HDGFL2) tightly binds HIV-1 integrase and stimulates its strand-transfer activity in vitro; recombinant HRP-2 efficiently reconstitutes the in vitro activity of HIV-1 preintegration complexes (PICs) disrupted by high-salt treatment, requiring both the IN-binding and DNA-binding activities.","method":"In vitro PIC reconstitution assay, recombinant protein binding, siRNA knockdown of HRP-2 and/or LEDGF/p75 in HeLa-P4 cells","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutational analysis of binding domains, single lab with orthogonal methods","pmids":["16337983"],"is_preprint":false},{"year":2012,"finding":"HRP-2 (HDGFL2) determines HIV-1 integration site selection in LEDGF/p75-depleted cells; HRP-2 overexpression in LEDGF/p75 KO cells rescues integration frequency in RefSeq genes to wild-type levels, while additional HRP-2 knockdown in LEDGF/p75-depleted cells shifts integration distribution toward random, demonstrating HRP-2 as an alternative chromatin-tethering cofactor for HIV-1 IN.","method":"LEDGF/p75 KO and HRP-2 KD cell lines, genome-wide HIV-1 integration site sequencing, HRP-2 overexpression rescue experiments","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO/KD with genome-wide integration site mapping plus overexpression rescue, replicated across multiple labs","pmids":["23046603"],"is_preprint":false},{"year":2012,"finding":"In Psip1/Hdgfrp2 double-knockout mouse cells, disruption of Hdgfrp2 in Psip1 KO cells yields additional defects in efficiency and specificity of HIV-1 integration beyond those seen in Psip1 KO alone; ectopic expression of either LEDGF/p75 or HRP-2 largely restores these deficits, confirming that HRP-2 contributes to integration targeting in vivo.","method":"Hdgfrp2 and Psip1/Hdgfrp2 double-KO mouse-derived cells infected with HIV-1, integration site sequencing, ectopic re-expression","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse genetic KO models with integration-site sequencing and rescue, multiple orthogonal methods in single rigorous study","pmids":["23042676"],"is_preprint":false},{"year":2020,"finding":"HRP2 (HDGFL2) acts as a key regulator of myogenic differentiation: through its PWWP domain it preferentially binds H3K36me2-marked chromatin, and through its IBD it directly interacts with the BAF chromatin remodeling complex subunit DPF3a (BAF45c), thereby recruiting BRG1 (the BAF ATPase) to increase chromatin accessibility at myogenic gene loci and activate their transcription.","method":"siRNA screening, CRISPR/Cas9 knockout in mice (impaired muscle regeneration phenotype), co-immunoprecipitation, recombinant protein binding, ChIP-seq, ATAC-seq, RNA-seq","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including KO mouse phenotype, direct protein interaction, ChIP-seq, ATAC-seq, and transcriptomics in a single study","pmids":["32459350"],"is_preprint":false},{"year":2022,"finding":"HRP2 (HDGFL2) recognizes H3K36me2 via its PWWP domain and recruits the histone demethylase MINA to remove H3K27me3 at target loci; knockdown of HRP2 augments H3K27me3 levels, promoting transcriptome alterations that support cell survival and restrict ER stress, thereby conferring resistance to proteasome inhibitors in multiple myeloma with t(4;14).","method":"CRISPR/Cas9 sgRNA library screen, HRP2 knockdown in MM cells, H3K27me3 ChIP, in vitro and in vivo bortezomib sensitivity assays, tazemetostat combination treatment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus mechanistic validation with ChIP, KD/OE, and in vivo mouse model, multiple orthogonal methods","pmids":["35166240"],"is_preprint":false},{"year":2015,"finding":"HRP-2 (HDGFL2) acts as an oncogene in hepatocellular carcinoma: it promotes cell growth in vitro and xenograft tumor growth in vivo; by protein affinity purification it interacts with proteins involved in transcription elongation/processing including RNA processing regulator IWS1, and positively regulates Cyclin D1 mRNA levels, suggesting a role as an mRNA processing co-factor.","method":"Overexpression and knockdown in HCC cells, xenograft mouse model, protein affinity purification, co-localization with IWS1","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single pulldown for IWS1 interaction, supported by in vivo xenograft and mRNA level readout, single lab","pmids":["25689719"],"is_preprint":false},{"year":2015,"finding":"Hdgfrp2 knockout mice develop normally and are fertile, but Psip1/Hdgfrp2 double-deficient mice die at approximately embryonic day 13.5 with ventricular septal defect (VSD); RNA-seq of ventricular tissue from double-KO embryos revealed deregulation of TGF-β signaling pathway but not global RNA splicing, implicating TGF-β as a contributing mechanism to the cardiac morphogenesis defect.","method":"Conditional and systemic gene knockout in mice, histological examination, RNA-sequencing of ventricular tissue, bioinformatic pathway analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with histology and RNA-seq, pathway placement is inferential (TGF-β speculative), single lab","pmids":["26367869"],"is_preprint":false},{"year":2021,"finding":"HRP-2 (HDGFL2) interacts with MLL (KMT2A) through a conserved interface (demonstrated by co-immunoprecipitation and validated by NMR using recombinant proteins), though this interaction is less dependent on menin than the MLL-LEDGF/p75 interaction; HRP-2 knockout mice show only increased peripheral blood neutrophils; depletion of HRP-2 in leukemic cell lines reduces colony formation independently of MLL rearrangements, but HRP-2 is dispensable for MLL-ENL-driven leukemic transformation of primary murine cells.","method":"Co-immunoprecipitation, NMR with recombinant proteins, systemic KO mouse model (hematopoiesis analysis), lentiviral miRNA-mediated KD in leukemic cell lines, colony formation assay, MLL-ENL transformation of primary murine cells","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — NMR structural validation of protein-protein interaction plus genetic KO mouse and cellular KD assays with functional readouts, single lab but multiple orthogonal methods","pmids":["33477970"],"is_preprint":false},{"year":2012,"finding":"HRP-2 (HDGFL2) forms heteromers with HDGF; a previously unknown splice isoform of HRP-2 (isoform c, with a 53-amino acid deletion in the hath region) preferentially interacts with a processed form of HDGF and, unlike other HRP-2 isoforms, binds to chromatin in a pattern similar to LEDGF/p75, with potential consequences for HIV integration.","method":"Co-immunoprecipitation of endogenous and overexpressed proteins, identification of new HRP-2 splice variant by RT-PCR/sequencing, chromatin binding assay, confocal microscopy","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and direct chromatin binding assay, single lab, two orthogonal methods","pmids":["22212508"],"is_preprint":false},{"year":2021,"finding":"HRP2 (HDGFL2) associates with M-phase phosphoprotein 8 (MPP8), a component of the human silencing hub (HUSH) complex; HRP2 colocalizes with MPP8 at the E-cadherin gene locus, suggesting a role in heterochromatin-related gene silencing and cancer cell plasticity.","method":"OBOC combinatorial screening to identify peptidomimetic MPP8 chromodomain ligand (UNC5246), biotinylated UNC5246 chemoproteomics pulldown, colocalization by ChIP at E-cadherin locus","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — chemical proteomics pulldown identifies interaction, confirmed by ChIP colocalization, single lab","pmids":["34415726"],"is_preprint":false},{"year":2022,"finding":"LEDGF/p75 and HDGFL2 (HRP-2) together largely account for allosteric integrase inhibitor (ALLINI)-mediated HIV-1 integration retargeting away from speckle-associated domain genes during early infection; double KO of both factors phenocopies ALLINI-treated cells in integration site distribution.","method":"LEDGF/p75 and HDGFL2 single and double KO cells, HIV-1 infection with ALLINI treatment, genome-wide integration site mapping","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic double-KO with genome-wide integration site sequencing and pharmacological perturbation, single lab with rigorous controls","pmids":["36146690"],"is_preprint":false},{"year":2024,"finding":"HDGFL2 PWWP domain recognizes methylated histones to recruit homologous recombination repair proteins to damaged silent chromatin genes; fragment-based screening identified two small-molecule inhibitors (varenicline and BPP) that engage the aromatic cage of the HDGFRP2 PWWP domain via distinct binding mechanisms, as revealed by X-ray co-crystal structures.","method":"Fragment-based screening, X-ray crystallography of HDGFRP2 PWWP domain in complex with inhibitors, biochemical binding assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of protein-ligand complexes with defined aromatic cage binding mechanism, single lab","pmids":["39031937"],"is_preprint":false},{"year":2024,"finding":"TDP-43 dysfunction leads to production of cryptic proteins from the HDGFL2 locus, which can serve as markers of TDP-43 pathology in neurodegenerative diseases.","method":"Detection of HDGFL2 cryptic proteins in patient samples and disease models with TDP-43 pathology","journal":"Molecular neurodegeneration","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, abstract provides minimal mechanistic detail about the production mechanism or functional consequence of the cryptic proteins","pmids":["38539264"],"is_preprint":false},{"year":2025,"finding":"HRP2 (HDGFL2) depletion in multiple myeloma cells results in elevated acetylation of H3K27 (H3K27Ac) and enhanced chromatin accessibility and transcriptional elongation of the MICU1 gene, leading to increased MICU1 expression, reduced Ca2+ overload-induced mitochondrial damage, and bortezomib resistance; MICU1 suppression restores BTZ sensitivity both in vitro and in a mouse model.","method":"BTZ-resistant MM cell line generation, HRP2 KO/KD and OE, H3K27Ac ChIP, ATAC-seq, in vivo mouse MM model, MICU1 inhibition rescue experiments","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and ATAC-seq mechanistic readouts with in vivo validation, single lab","pmids":["40058268"],"is_preprint":false}],"current_model":"HDGFL2 (HRP2) is a chromatin-associated protein that, via its PWWP domain, reads H3K36me2-marked chromatin and, via its integrase-binding domain (IBD), recruits both HIV-1 integrase (acting as an alternative tethering cofactor to LEDGF/p75 for viral integration into active genes) and chromatin remodeling/epigenetic complexes (BAF complex through DPF3a, histone demethylase MINA, and the HUSH complex through MPP8); in normal development it is required alongside LEDGF/p75 for cardiac morphogenesis, in muscle it activates myogenic gene transcription by increasing chromatin accessibility, and in multiple myeloma it suppresses chemoresistance by maintaining H3K27me3 levels via MINA recruitment and by restricting MICU1-mediated calcium homeostasis."},"narrative":{"mechanistic_narrative":"HDGFL2 (HRP-2) is a chromatin-associated reader-adaptor that couples recognition of methylated histone marks to the recruitment of effector machineries governing transcription, genome silencing, DNA repair, and—when hijacked—retroviral integration [PMID:32459350, PMID:22396646]. Its PWWP domain preferentially engages H3K36me2-marked chromatin through a defined aromatic cage that has been resolved by X-ray crystallography in complex with small-molecule ligands, while its LEDGF/p75-like integrase-binding domain (IBD) provides the protein-protein interface that tethers effectors to those chromatin sites [PMID:32459350, PMID:39031937]. The IBD binds HIV-1 integrase, stimulates its strand-transfer activity, and reconstitutes salt-disrupted preintegration complexes in vitro; in cells lacking LEDGF/p75, HDGFL2 serves as an alternative chromatin-tethering cofactor that determines integration-site selection toward active genes, a role demonstrated by knockout, knockdown, overexpression rescue, and genome-wide integration mapping in human and mouse cells [PMID:16337983, PMID:23046603, PMID:23042676, PMID:36146690]. Through the same domains HDGFL2 recruits chromatin-remodeling and epigenetic complexes: it binds the BAF subunit DPF3a to deliver the BRG1 ATPase and open chromatin at myogenic loci, driving myogenic gene transcription and muscle regeneration [PMID:32459350], and it recruits the histone demethylase MINA to maintain H3K27me3 at target loci [PMID:35166240]. In t(4;14) multiple myeloma, loss of HDGFL2 elevates H3K27me3-opposing marks and chromatin accessibility—including derepression of MICU1—producing transcriptomic changes that limit ER stress and Ca2+-driven mitochondrial damage, thereby conferring proteasome-inhibitor resistance [PMID:35166240, PMID:40058268]. HDGFL2 additionally associates with the HUSH-complex subunit MPP8 and with MLL/KMT2A, linking it to heterochromatin-related gene silencing and leukemic colony formation [PMID:34415726, PMID:33477970]. Together with LEDGF/p75 it is required for cardiac morphogenesis, as Psip1/Hdgfrp2 double-deficient mice die with ventricular septal defects [PMID:26367869].","teleology":[{"year":2005,"claim":"Established the biochemical basis for HDGFL2 acting on HIV-1 integrase, answering whether it could directly modulate integration chemistry.","evidence":"In vitro PIC reconstitution and recombinant protein binding with domain mutants in HeLa-P4 cells","pmids":["16337983"],"confidence":"High","gaps":["Did not establish relative importance versus LEDGF/p75 in cells","Chromatin-tethering role not yet defined"]},{"year":2012,"claim":"Defined HDGFL2 as a functional backup tethering cofactor for HIV-1, resolving how viral integration persists when LEDGF/p75 is absent.","evidence":"LEDGF/p75 knockout human cells with HRP-2 knockdown, spreading infection and integration-site sequencing, overexpression rescue, plus Psip1/Hdgfrp2 double-KO mouse cells and heteromer/splice-isoform analyses","pmids":["22396646","23046603","23042676","22212508"],"confidence":"High","gaps":["The endogenous (non-viral) chromatin function still undefined at this stage","Which histone mark directs HDGFL2 tethering not yet shown"]},{"year":2020,"claim":"Identified HDGFL2 as a histone-mark reader and chromatin-remodeler adaptor in a physiological context, linking PWWP recognition of H3K36me2 to transcriptional activation.","evidence":"CRISPR knockout mice with muscle-regeneration phenotype, Co-IP and recombinant binding to DPF3a/BAF, ChIP-seq, ATAC-seq, RNA-seq","pmids":["32459350"],"confidence":"High","gaps":["Generality of the H3K36me2-PWWP mechanism beyond muscle not addressed","Direct BRG1 recruitment dynamics not kinetically resolved"]},{"year":2015,"claim":"Probed HDGFL2 roles in tissue development and cancer, indicating a transcription/processing co-factor activity and a requirement in cardiac morphogenesis.","evidence":"Psip1/Hdgfrp2 double-KO mice with VSD and ventricular RNA-seq; HCC overexpression/knockdown with xenografts and IWS1 affinity purification","pmids":["26367869","25689719"],"confidence":"Medium","gaps":["TGF-β pathway link is inferential from expression data","IWS1 interaction rests on a single pulldown without reciprocal validation"]},{"year":2021,"claim":"Expanded the HDGFL2 interactome to silencing and leukemia-associated complexes, addressing what effectors it recruits beyond BAF.","evidence":"Chemoproteomic pulldown and ChIP colocalization with MPP8/HUSH at E-cadherin; Co-IP and NMR validation of MLL/KMT2A interaction with KO mouse hematopoiesis and leukemic colony assays","pmids":["34415726","33477970"],"confidence":"High","gaps":["Functional consequence of HUSH association on silencing not directly tested","HDGFL2 dispensable for MLL-ENL transformation, leaving its leukemic role partial"]},{"year":2022,"claim":"Defined a tumor-suppressive epigenetic axis, explaining how HDGFL2 loss drives proteasome-inhibitor resistance in multiple myeloma.","evidence":"Genome-wide CRISPR screen, HRP2 knockdown, H3K27me3 ChIP, MINA recruitment, in vitro/in vivo bortezomib and tazemetostat assays; double-KO integration mapping under ALLINI treatment","pmids":["35166240","36146690"],"confidence":"High","gaps":["Mechanism of MINA recruitment by the IBD not structurally resolved","Direct demethylase coupling versus indirect effects on H3K27me3 not fully separated"]},{"year":2024,"claim":"Provided structural and additional functional dimensions—an inhibitable PWWP aromatic cage, a DNA-repair recruitment role, and a TDP-43-linked cryptic-protein readout.","evidence":"Fragment-based screening with X-ray co-crystal structures of the PWWP domain; recruitment of HR repair proteins to damaged silent chromatin; cryptic HDGFL2 protein detection in TDP-43 pathology","pmids":["39031937","38539264"],"confidence":"Medium","gaps":["DNA-repair recruitment mechanism not biochemically dissected","Cryptic-protein finding (Low confidence) lacks mechanistic detail on production and function"]},{"year":2025,"claim":"Connected HDGFL2 chromatin control to mitochondrial calcium handling, identifying MICU1 derepression as a resistance effector.","evidence":"BTZ-resistant MM cells with HRP2 KO/KD/OE, H3K27Ac ChIP, ATAC-seq, in vivo model, and MICU1-inhibition rescue","pmids":["40058268"],"confidence":"Medium","gaps":["Direct versus indirect regulation of the MICU1 locus by HDGFL2 not fully separated","Single-lab finding without independent replication"]},{"year":null,"claim":"How HDGFL2 selects among its distinct effector partners (BAF, MINA, HUSH, MLL, HIV integrase) at specific chromatin sites, and what governs this partner choice, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-dependent effector selection","Structural basis of IBD-effector versus IBD-integrase discrimination not defined","In vivo physiological role of endogenous HDGFL2 outside muscle and heart underexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4,5,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,0,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4,9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,5]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,5,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,5,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["LEDGF/P75","DPF3","MINA","MPP8","KMT2A","HDGF","IWS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z4V5","full_name":"Hepatoma-derived growth factor-related protein 2","aliases":["Hepatoma-derived growth factor 2","HDGF-2"],"length_aa":671,"mass_kda":74.3,"function":"Acts as an epigenetic regulator of myogenesis in cooperation with DPF3a (isoform 2 of DPF3/BAF45C) (PubMed:32459350). Associates with the BAF complex via its interaction with DPF3a and HDGFL2-DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of SMARCA4/BRG1/BAF190A (ATPase subunit of the BAF complex) to myogenic gene promoters (PubMed:32459350). Promotes the repair of DNA double-strand breaks (DSBs) through the homologous recombination pathway by facilitating the recruitment of the DNA endonuclease RBBP8 to the DSBs (PubMed:26721387). Preferentially binds to chromatin regions marked by H3K9me3, H3K27me3 and H3K36me2 (PubMed:26721387, PubMed:32459350). Involved in cellular growth control, through the regulation of cyclin D1 expression (PubMed:25689719)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q7Z4V5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDGFL2","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HDGFL2","total_profiled":1310},"omim":[{"mim_id":"617884","title":"HEPATOMA-DERIVED GROWTH FACTOR-LIKE PROTEIN 2; HDGFL2","url":"https://www.omim.org/entry/617884"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"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/HDGFL2"},"hgnc":{"alias_symbol":["HRP2","Hdgfrp2"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z4V5","domains":[{"cath_id":"2.30.30.140","chopping":"10-88","consensus_level":"high","plddt":89.8406,"start":10,"end":88},{"cath_id":"1.20.930.10","chopping":"472-573","consensus_level":"high","plddt":82.7745,"start":472,"end":573},{"cath_id":"1.20.5","chopping":"318-356","consensus_level":"medium","plddt":86.3972,"start":318,"end":356}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4V5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4V5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4V5-F1-predicted_aligned_error_v6.png","plddt_mean":59.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDGFL2","jax_strain_url":"https://www.jax.org/strain/search?query=HDGFL2"},"sequence":{"accession":"Q7Z4V5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z4V5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z4V5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4V5"}},"corpus_meta":[{"pmid":"7906328","id":"PMC_7906328","title":"Diagnosis 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domain.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/39031937","citation_count":0,"is_preprint":false},{"pmid":"42024904","id":"PMC_42024904","title":"Are HRP2/3 deletions silently crippling malaria rapid diagnostic tests?","date":"2026","source":"The Indian journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/42024904","citation_count":0,"is_preprint":false},{"pmid":"41141431","id":"PMC_41141431","title":"High Prevalence of Plasmodium falciparum HRP2/3 Gene Deletions in Ethiopia: Implications for Malaria Diagnosis and Treatment-A Systematic Review and Meta-Analysis.","date":"2025","source":"The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale","url":"https://pubmed.ncbi.nlm.nih.gov/41141431","citation_count":0,"is_preprint":false},{"pmid":"40693034","id":"PMC_40693034","title":"Undetected Plasmodium malariae and P. ovale infections in HRP2 RDT-positive children with uncomplicated malaria in Nanoro, Burkina Faso.","date":"2025","source":"MalariaWorld journal","url":"https://pubmed.ncbi.nlm.nih.gov/40693034","citation_count":0,"is_preprint":false},{"pmid":"41777401","id":"PMC_41777401","title":"Diagnostic challenges in malaria detection: A comparative diagnostic performance of HRP2-based rapid diagnostic tests, microscopy, and PCR at Bichena primary hospital, Northwest Ethiopia.","date":"2026","source":"Parasite epidemiology and control","url":"https://pubmed.ncbi.nlm.nih.gov/41777401","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.15.25333763","title":"Dynamic programming model for pattern recognition on the PfHRP2 sequence variants: a smart approach to improve malaria immunodiagnostics","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.15.25333763","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59192,"output_tokens":4157,"usd":0.119966,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11999,"output_tokens":3532,"usd":0.074148,"stage2_stop_reason":"end_turn"},"total_usd":0.194114,"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\": 2012,\n \"finding\": \"HRP-2 (HDGFL2) contains an integrase-binding domain (IBD) identical to that of LEDGF/p75 and can bind HIV-1 integrase (IN), stimulating its integration activity; in LEDGF/p75 knockout cells, HRP-2 mediates residual HIV-1 replication and partially compensates for LEDGF/p75 loss in tethering the pre-integration complex to chromatin.\",\n \"method\": \"Human somatic LEDGF/p75 knockout cell line (homologous recombination), spreading HIV-1 infection assay, siRNA knockdown of HRP-2, LEDIN inhibitor competition assay\",\n \"journal\": \"PLoS pathogens\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic KO and KD experiments in human cells with direct functional HIV replication and integration readouts, replicated across multiple labs (PMIDs 22396646, 23042676, 23046603)\",\n \"pmids\": [\"22396646\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2005,\n \"finding\": \"HRP-2 (HDGFL2) tightly binds HIV-1 integrase and stimulates its strand-transfer activity in vitro; recombinant HRP-2 efficiently reconstitutes the in vitro activity of HIV-1 preintegration complexes (PICs) disrupted by high-salt treatment, requiring both the IN-binding and DNA-binding activities.\",\n \"method\": \"In vitro PIC reconstitution assay, recombinant protein binding, siRNA knockdown of HRP-2 and/or LEDGF/p75 in HeLa-P4 cells\",\n \"journal\": \"Virology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutational analysis of binding domains, single lab with orthogonal methods\",\n \"pmids\": [\"16337983\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"HRP-2 (HDGFL2) determines HIV-1 integration site selection in LEDGF/p75-depleted cells; HRP-2 overexpression in LEDGF/p75 KO cells rescues integration frequency in RefSeq genes to wild-type levels, while additional HRP-2 knockdown in LEDGF/p75-depleted cells shifts integration distribution toward random, demonstrating HRP-2 as an alternative chromatin-tethering cofactor for HIV-1 IN.\",\n \"method\": \"LEDGF/p75 KO and HRP-2 KD cell lines, genome-wide HIV-1 integration site sequencing, HRP-2 overexpression rescue experiments\",\n \"journal\": \"Retrovirology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — genetic KO/KD with genome-wide integration site mapping plus overexpression rescue, replicated across multiple labs\",\n \"pmids\": [\"23046603\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"In Psip1/Hdgfrp2 double-knockout mouse cells, disruption of Hdgfrp2 in Psip1 KO cells yields additional defects in efficiency and specificity of HIV-1 integration beyond those seen in Psip1 KO alone; ectopic expression of either LEDGF/p75 or HRP-2 largely restores these deficits, confirming that HRP-2 contributes to integration targeting in vivo.\",\n \"method\": \"Hdgfrp2 and Psip1/Hdgfrp2 double-KO mouse-derived cells infected with HIV-1, integration site sequencing, ectopic re-expression\",\n \"journal\": \"Nucleic acids research\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — mouse genetic KO models with integration-site sequencing and rescue, multiple orthogonal methods in single rigorous study\",\n \"pmids\": [\"23042676\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2020,\n \"finding\": \"HRP2 (HDGFL2) acts as a key regulator of myogenic differentiation: through its PWWP domain it preferentially binds H3K36me2-marked chromatin, and through its IBD it directly interacts with the BAF chromatin remodeling complex subunit DPF3a (BAF45c), thereby recruiting BRG1 (the BAF ATPase) to increase chromatin accessibility at myogenic gene loci and activate their transcription.\",\n \"method\": \"siRNA screening, CRISPR/Cas9 knockout in mice (impaired muscle regeneration phenotype), co-immunoprecipitation, recombinant protein binding, ChIP-seq, ATAC-seq, RNA-seq\",\n \"journal\": \"Nucleic acids research\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including KO mouse phenotype, direct protein interaction, ChIP-seq, ATAC-seq, and transcriptomics in a single study\",\n \"pmids\": [\"32459350\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"HRP2 (HDGFL2) recognizes H3K36me2 via its PWWP domain and recruits the histone demethylase MINA to remove H3K27me3 at target loci; knockdown of HRP2 augments H3K27me3 levels, promoting transcriptome alterations that support cell survival and restrict ER stress, thereby conferring resistance to proteasome inhibitors in multiple myeloma with t(4;14).\",\n \"method\": \"CRISPR/Cas9 sgRNA library screen, HRP2 knockdown in MM cells, H3K27me3 ChIP, in vitro and in vivo bortezomib sensitivity assays, tazemetostat combination treatment\",\n \"journal\": \"The Journal of clinical investigation\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus mechanistic validation with ChIP, KD/OE, and in vivo mouse model, multiple orthogonal methods\",\n \"pmids\": [\"35166240\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"HRP-2 (HDGFL2) acts as an oncogene in hepatocellular carcinoma: it promotes cell growth in vitro and xenograft tumor growth in vivo; by protein affinity purification it interacts with proteins involved in transcription elongation/processing including RNA processing regulator IWS1, and positively regulates Cyclin D1 mRNA levels, suggesting a role as an mRNA processing co-factor.\",\n \"method\": \"Overexpression and knockdown in HCC cells, xenograft mouse model, protein affinity purification, co-localization with IWS1\",\n \"journal\": \"Biochemical and biophysical research communications\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — single pulldown for IWS1 interaction, supported by in vivo xenograft and mRNA level readout, single lab\",\n \"pmids\": [\"25689719\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"Hdgfrp2 knockout mice develop normally and are fertile, but Psip1/Hdgfrp2 double-deficient mice die at approximately embryonic day 13.5 with ventricular septal defect (VSD); RNA-seq of ventricular tissue from double-KO embryos revealed deregulation of TGF-β signaling pathway but not global RNA splicing, implicating TGF-β as a contributing mechanism to the cardiac morphogenesis defect.\",\n \"method\": \"Conditional and systemic gene knockout in mice, histological examination, RNA-sequencing of ventricular tissue, bioinformatic pathway analysis\",\n \"journal\": \"PloS one\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with histology and RNA-seq, pathway placement is inferential (TGF-β speculative), single lab\",\n \"pmids\": [\"26367869\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"HRP-2 (HDGFL2) interacts with MLL (KMT2A) through a conserved interface (demonstrated by co-immunoprecipitation and validated by NMR using recombinant proteins), though this interaction is less dependent on menin than the MLL-LEDGF/p75 interaction; HRP-2 knockout mice show only increased peripheral blood neutrophils; depletion of HRP-2 in leukemic cell lines reduces colony formation independently of MLL rearrangements, but HRP-2 is dispensable for MLL-ENL-driven leukemic transformation of primary murine cells.\",\n \"method\": \"Co-immunoprecipitation, NMR with recombinant proteins, systemic KO mouse model (hematopoiesis analysis), lentiviral miRNA-mediated KD in leukemic cell lines, colony formation assay, MLL-ENL transformation of primary murine cells\",\n \"journal\": \"Cells\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1-2 / Moderate — NMR structural validation of protein-protein interaction plus genetic KO mouse and cellular KD assays with functional readouts, single lab but multiple orthogonal methods\",\n \"pmids\": [\"33477970\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"HRP-2 (HDGFL2) forms heteromers with HDGF; a previously unknown splice isoform of HRP-2 (isoform c, with a 53-amino acid deletion in the hath region) preferentially interacts with a processed form of HDGF and, unlike other HRP-2 isoforms, binds to chromatin in a pattern similar to LEDGF/p75, with potential consequences for HIV integration.\",\n \"method\": \"Co-immunoprecipitation of endogenous and overexpressed proteins, identification of new HRP-2 splice variant by RT-PCR/sequencing, chromatin binding assay, confocal microscopy\",\n \"journal\": \"The FEBS journal\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and direct chromatin binding assay, single lab, two orthogonal methods\",\n \"pmids\": [\"22212508\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"HRP2 (HDGFL2) associates with M-phase phosphoprotein 8 (MPP8), a component of the human silencing hub (HUSH) complex; HRP2 colocalizes with MPP8 at the E-cadherin gene locus, suggesting a role in heterochromatin-related gene silencing and cancer cell plasticity.\",\n \"method\": \"OBOC combinatorial screening to identify peptidomimetic MPP8 chromodomain ligand (UNC5246), biotinylated UNC5246 chemoproteomics pulldown, colocalization by ChIP at E-cadherin locus\",\n \"journal\": \"ACS chemical biology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — chemical proteomics pulldown identifies interaction, confirmed by ChIP colocalization, single lab\",\n \"pmids\": [\"34415726\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"LEDGF/p75 and HDGFL2 (HRP-2) together largely account for allosteric integrase inhibitor (ALLINI)-mediated HIV-1 integration retargeting away from speckle-associated domain genes during early infection; double KO of both factors phenocopies ALLINI-treated cells in integration site distribution.\",\n \"method\": \"LEDGF/p75 and HDGFL2 single and double KO cells, HIV-1 infection with ALLINI treatment, genome-wide integration site mapping\",\n \"journal\": \"Viruses\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-KO with genome-wide integration site sequencing and pharmacological perturbation, single lab with rigorous controls\",\n \"pmids\": [\"36146690\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"HDGFL2 PWWP domain recognizes methylated histones to recruit homologous recombination repair proteins to damaged silent chromatin genes; fragment-based screening identified two small-molecule inhibitors (varenicline and BPP) that engage the aromatic cage of the HDGFRP2 PWWP domain via distinct binding mechanisms, as revealed by X-ray co-crystal structures.\",\n \"method\": \"Fragment-based screening, X-ray crystallography of HDGFRP2 PWWP domain in complex with inhibitors, biochemical binding assays\",\n \"journal\": \"FEBS letters\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of protein-ligand complexes with defined aromatic cage binding mechanism, single lab\",\n \"pmids\": [\"39031937\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"TDP-43 dysfunction leads to production of cryptic proteins from the HDGFL2 locus, which can serve as markers of TDP-43 pathology in neurodegenerative diseases.\",\n \"method\": \"Detection of HDGFL2 cryptic proteins in patient samples and disease models with TDP-43 pathology\",\n \"journal\": \"Molecular neurodegeneration\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 3 / Weak — single study, abstract provides minimal mechanistic detail about the production mechanism or functional consequence of the cryptic proteins\",\n \"pmids\": [\"38539264\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"HRP2 (HDGFL2) depletion in multiple myeloma cells results in elevated acetylation of H3K27 (H3K27Ac) and enhanced chromatin accessibility and transcriptional elongation of the MICU1 gene, leading to increased MICU1 expression, reduced Ca2+ overload-induced mitochondrial damage, and bortezomib resistance; MICU1 suppression restores BTZ sensitivity both in vitro and in a mouse model.\",\n \"method\": \"BTZ-resistant MM cell line generation, HRP2 KO/KD and OE, H3K27Ac ChIP, ATAC-seq, in vivo mouse MM model, MICU1 inhibition rescue experiments\",\n \"journal\": \"Neoplasia (New York, N.Y.)\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and ATAC-seq mechanistic readouts with in vivo validation, single lab\",\n \"pmids\": [\"40058268\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"HDGFL2 (HRP2) is a chromatin-associated protein that, via its PWWP domain, reads H3K36me2-marked chromatin and, via its integrase-binding domain (IBD), recruits both HIV-1 integrase (acting as an alternative tethering cofactor to LEDGF/p75 for viral integration into active genes) and chromatin remodeling/epigenetic complexes (BAF complex through DPF3a, histone demethylase MINA, and the HUSH complex through MPP8); in normal development it is required alongside LEDGF/p75 for cardiac morphogenesis, in muscle it activates myogenic gene transcription by increasing chromatin accessibility, and in multiple myeloma it suppresses chemoresistance by maintaining H3K27me3 levels via MINA recruitment and by restricting MICU1-mediated calcium homeostasis.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"HDGFL2 (HRP-2) is a chromatin-associated reader-adaptor that couples recognition of methylated histone marks to the recruitment of effector machineries governing transcription, genome silencing, DNA repair, and—when hijacked—retroviral integration [#4, #0]. Its PWWP domain preferentially engages H3K36me2-marked chromatin through a defined aromatic cage that has been resolved by X-ray crystallography in complex with small-molecule ligands, while its LEDGF/p75-like integrase-binding domain (IBD) provides the protein-protein interface that tethers effectors to those chromatin sites [#4, #12]. The IBD binds HIV-1 integrase, stimulates its strand-transfer activity, and reconstitutes salt-disrupted preintegration complexes in vitro; in cells lacking LEDGF/p75, HDGFL2 serves as an alternative chromatin-tethering cofactor that determines integration-site selection toward active genes, a role demonstrated by knockout, knockdown, overexpression rescue, and genome-wide integration mapping in human and mouse cells [#1, #2, #3, #11]. Through the same domains HDGFL2 recruits chromatin-remodeling and epigenetic complexes: it binds the BAF subunit DPF3a to deliver the BRG1 ATPase and open chromatin at myogenic loci, driving myogenic gene transcription and muscle regeneration [#4], and it recruits the histone demethylase MINA to maintain H3K27me3 at target loci [#5]. In t(4;14) multiple myeloma, loss of HDGFL2 elevates H3K27me3-opposing marks and chromatin accessibility—including derepression of MICU1—producing transcriptomic changes that limit ER stress and Ca2+-driven mitochondrial damage, thereby conferring proteasome-inhibitor resistance [#5, #14]. HDGFL2 additionally associates with the HUSH-complex subunit MPP8 and with MLL/KMT2A, linking it to heterochromatin-related gene silencing and leukemic colony formation [#10, #8]. Together with LEDGF/p75 it is required for cardiac morphogenesis, as Psip1/Hdgfrp2 double-deficient mice die with ventricular septal defects [#7].\",\n \"teleology\": [\n {\n \"year\": 2005,\n \"claim\": \"Established the biochemical basis for HDGFL2 acting on HIV-1 integrase, answering whether it could directly modulate integration chemistry.\",\n \"evidence\": \"In vitro PIC reconstitution and recombinant protein binding with domain mutants in HeLa-P4 cells\",\n \"pmids\": [\"16337983\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Did not establish relative importance versus LEDGF/p75 in cells\", \"Chromatin-tethering role not yet defined\"]\n },\n {\n \"year\": 2012,\n \"claim\": \"Defined HDGFL2 as a functional backup tethering cofactor for HIV-1, resolving how viral integration persists when LEDGF/p75 is absent.\",\n \"evidence\": \"LEDGF/p75 knockout human cells with HRP-2 knockdown, spreading infection and integration-site sequencing, overexpression rescue, plus Psip1/Hdgfrp2 double-KO mouse cells and heteromer/splice-isoform analyses\",\n \"pmids\": [\"22396646\", \"23046603\", \"23042676\", \"22212508\"],\n \"confidence\": \"High\",\n \"gaps\": [\"The endogenous (non-viral) chromatin function still undefined at this stage\", \"Which histone mark directs HDGFL2 tethering not yet shown\"]\n },\n {\n \"year\": 2020,\n \"claim\": \"Identified HDGFL2 as a histone-mark reader and chromatin-remodeler adaptor in a physiological context, linking PWWP recognition of H3K36me2 to transcriptional activation.\",\n \"evidence\": \"CRISPR knockout mice with muscle-regeneration phenotype, Co-IP and recombinant binding to DPF3a/BAF, ChIP-seq, ATAC-seq, RNA-seq\",\n \"pmids\": [\"32459350\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Generality of the H3K36me2-PWWP mechanism beyond muscle not addressed\", \"Direct BRG1 recruitment dynamics not kinetically resolved\"]\n },\n {\n \"year\": 2015,\n \"claim\": \"Probed HDGFL2 roles in tissue development and cancer, indicating a transcription/processing co-factor activity and a requirement in cardiac morphogenesis.\",\n \"evidence\": \"Psip1/Hdgfrp2 double-KO mice with VSD and ventricular RNA-seq; HCC overexpression/knockdown with xenografts and IWS1 affinity purification\",\n \"pmids\": [\"26367869\", \"25689719\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"TGF-β pathway link is inferential from expression data\", \"IWS1 interaction rests on a single pulldown without reciprocal validation\"]\n },\n {\n \"year\": 2021,\n \"claim\": \"Expanded the HDGFL2 interactome to silencing and leukemia-associated complexes, addressing what effectors it recruits beyond BAF.\",\n \"evidence\": \"Chemoproteomic pulldown and ChIP colocalization with MPP8/HUSH at E-cadherin; Co-IP and NMR validation of MLL/KMT2A interaction with KO mouse hematopoiesis and leukemic colony assays\",\n \"pmids\": [\"34415726\", \"33477970\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Functional consequence of HUSH association on silencing not directly tested\", \"HDGFL2 dispensable for MLL-ENL transformation, leaving its leukemic role partial\"]\n },\n {\n \"year\": 2022,\n \"claim\": \"Defined a tumor-suppressive epigenetic axis, explaining how HDGFL2 loss drives proteasome-inhibitor resistance in multiple myeloma.\",\n \"evidence\": \"Genome-wide CRISPR screen, HRP2 knockdown, H3K27me3 ChIP, MINA recruitment, in vitro/in vivo bortezomib and tazemetostat assays; double-KO integration mapping under ALLINI treatment\",\n \"pmids\": [\"35166240\", \"36146690\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Mechanism of MINA recruitment by the IBD not structurally resolved\", \"Direct demethylase coupling versus indirect effects on H3K27me3 not fully separated\"]\n },\n {\n \"year\": 2024,\n \"claim\": \"Provided structural and additional functional dimensions—an inhibitable PWWP aromatic cage, a DNA-repair recruitment role, and a TDP-43-linked cryptic-protein readout.\",\n \"evidence\": \"Fragment-based screening with X-ray co-crystal structures of the PWWP domain; recruitment of HR repair proteins to damaged silent chromatin; cryptic HDGFL2 protein detection in TDP-43 pathology\",\n \"pmids\": [\"39031937\", \"38539264\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"DNA-repair recruitment mechanism not biochemically dissected\", \"Cryptic-protein finding (Low confidence) lacks mechanistic detail on production and function\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Connected HDGFL2 chromatin control to mitochondrial calcium handling, identifying MICU1 derepression as a resistance effector.\",\n \"evidence\": \"BTZ-resistant MM cells with HRP2 KO/KD/OE, H3K27Ac ChIP, ATAC-seq, in vivo model, and MICU1-inhibition rescue\",\n \"pmids\": [\"40058268\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direct versus indirect regulation of the MICU1 locus by HDGFL2 not fully separated\", \"Single-lab finding without independent replication\"]\n },\n {\n \"year\": null,\n \"claim\": \"How HDGFL2 selects among its distinct effector partners (BAF, MINA, HUSH, MLL, HIV integrase) at specific chromatin sites, and what governs this partner choice, remains unresolved.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"Medium\",\n \"gaps\": [\"No unifying model for context-dependent effector selection\", \"Structural basis of IBD-effector versus IBD-integrase discrimination not defined\", \"In vivo physiological role of endogenous HDGFL2 outside muscle and heart underexplored\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4, 5, 12]},\n {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 0, 2]},\n {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5]},\n {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4, 9, 10]},\n {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 5]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5, 10]},\n {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 6]},\n {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 5, 14]},\n {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7]}\n ],\n \"complexes\": [],\n \"partners\": [\"LEDGF/p75\", \"DPF3\", \"MINA\", \"MPP8\", \"KMT2A\", \"HDGF\", \"IWS1\"],\n \"other_free_text\": []\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}