Affinage

HP1BP3

Heterochromatin protein 1-binding protein 3 · UniProt Q5SSJ5

Round 2 corrected
Length
553 aa
Mass
61.2 kDa
Annotated
2026-04-28
43 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HP1BP3 is a histone H1-like linker histone variant that binds nucleosome core particles to form chromatosomes, maintains heterochromatin integrity, and regulates gene expression programs involved in cell proliferation, miRNA biogenesis, and imprinting. Its globular domain adopts a linker-histone fold and mediates chromatosome formation, with chromatin association regulated by the chaperones NPM1 and TAF-I; ChIP-seq shows preferential occupancy at loci bearing active histone marks, contrasting the inactive-locus preference of canonical H1.2 (PMID:20042602, PMID:40140990). HP1BP3 associates with the Drosha–DGCR8 microprocessor, directly binds pri-miRNAs, and is required for Drosha recruitment to actively transcribed miRNA loci, thereby coupling co-transcriptional pri-miRNA processing to chromatin (PMID:27425409). In vivo, Hp1bp3-knockout mice display neonatal lethality, proportionate dwarfism linked to a severely impaired endocrine IGF-1 axis, defective maternal behavior, and age-dependent cognitive decline (PMID:25662603, PMID:26402843, PMID:27460150, PMID:27470444).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 High

    Establishing that HP1BP3 is structurally and functionally a linker histone: NMR revealed a globular domain fold resembling canonical linker histones, and in vitro reconstitution showed it forms chromatosome-like structures protecting ~25 bp of linker DNA, while also directly binding HP1.

    Evidence NMR structure determination, MNase protection assay, and direct HP1-binding assay with reconstituted mononucleosomes

    PMID:20042602

    Open questions at the time
    • Genomic distribution of HP1BP3 on chromatin unknown
    • Chaperone-mediated regulation of HP1BP3-nucleosome binding not addressed
    • Functional consequences of HP1BP3 depletion not tested
  2. 2014 Medium

    Demonstrating that HP1BP3 is a dynamic chromatin component whose loss disrupts heterochromatin integrity during G1–S and promotes chromatin condensation under hypoxia, establishing functional roles in cell cycle regulation and stress-adaptive chromatin remodeling.

    Evidence Partial MNase/DNase digestion with iTRAQ quantitative proteomics, cell cycle analysis, and functional assays for viability/resistance under hypoxia

    PMID:24830416 PMID:25100860

    Open questions at the time
    • Direct molecular mechanism linking HP1BP3 to G1 duration control not defined
    • Hypoxia-driven chromatin condensation mechanism (signaling pathway activating HP1BP3) not resolved
  3. 2015 High

    In vivo validation that HP1BP3 is essential for organismal growth and viability: knockout mice exhibit 60% neonatal lethality, proportionate dwarfism with impaired bone, and a 60% reduction in circulating IGF-1 with elevated IGFBPs, placing HP1BP3 upstream of the endocrine IGF-1 axis through hepatic transcriptional regulation.

    Evidence Hp1bp3-knockout mice, microCT, primary cell differentiation, ELISA, qRT-PCR; FRAP and transcriptional profiling in HeLa cells

    PMID:25662603 PMID:26402843

    Open questions at the time
    • Direct chromatin targets through which HP1BP3 controls Igf1/Igfbp transcription not identified
    • Cause of neonatal lethality beyond growth retardation not established
  4. 2016 High

    Revealing a non-canonical chromatin function: HP1BP3 physically associates with the Drosha–DGCR8 microprocessor, co-localizes with Drosha genome-wide at active miRNA loci, directly binds pri-miRNAs, and is required for their chromatin retention and co-transcriptional processing.

    Evidence Co-IP, ChIP-seq, RNA immunoprecipitation, knockdown with miRNA profiling

    PMID:27425409

    Open questions at the time
    • Structural basis of HP1BP3–Drosha interaction not determined
    • Whether linker-histone and microprocessor functions are mutually exclusive or simultaneous on the same loci is unknown
  5. 2016 Medium

    Extending in vivo roles to the nervous system: Hp1bp3 deletion recapitulates age-related cognitive impairment in mice, and HP1BP3 protein levels are reduced in hippocampi of cognitively impaired elderly humans; knockout females also show specific maternal behavior deficits.

    Evidence Knockout mouse behavioral testing, western blot quantification in human hippocampal tissue, pup-retrieval and anxiety tests with co-fostering rescue

    PMID:27460150 PMID:27470444

    Open questions at the time
    • Molecular targets and chromatin changes in hippocampal neurons underlying cognitive phenotype not identified
    • Causal versus correlative nature of reduced HP1BP3 in human cognitive aging not resolved
  6. 2022 Medium

    Connecting HP1BP3 to oncogenic chromatin remodeling: EZH2 physically interacts with HP1BP3 in glioma stem cells, impairing H3K9 methylation; together they co-activate WNT7B to drive proliferation and temozolomide resistance, which is pharmacologically reversible.

    Evidence Reciprocal Co-IP/mass spectrometry, overexpression/knockdown functional assays, pharmacological inhibition with LGK974

    PMID:36517590

    Open questions at the time
    • Mechanism by which HP1BP3–EZH2 interaction impairs H3K9 methylation is unclear
    • Whether WNT7B co-activation is direct (at the promoter) or indirect not fully established
  7. 2024 Medium

    Demonstrating a role in genomic imprinting: PGC7 binds the HP1BP3 globular domain and is recruited by HP1BP3 to the Meg3 differentially methylated region, where their cooperative occupancy antagonizes DNMT3A and prevents aberrant DNA hypermethylation.

    Evidence Domain-mapped Co-IP, ChIP at Meg3-DMR, bisulfite sequencing, DNMT3A ChIP upon HP1BP3/PGC7 knockdown

    PMID:39422314

    Open questions at the time
    • Whether HP1BP3–PGC7 protection operates at other imprinted loci genome-wide not tested
    • Mechanism of chromosome decondensation upon HP1BP3/PGC7 depletion not resolved
  8. 2025 High

    Completing the mechanistic picture of HP1BP3 as a bona fide linker histone variant: biochemical reconstitution confirmed one-to-one chromatosome binding, identified NPM1 and TAF-I as linker histone chaperones that regulate this activity, and ChIP-seq revealed a preference for active chromatin loci — the opposite of canonical H1.2.

    Evidence Biochemical NCP-binding/chromatosome reconstitution, Co-IP for chaperone interactions, ChIP-seq, NPM1/TAF-I knockdown

    PMID:40140990

    Open questions at the time
    • Structural basis of how NPM1/TAF-I chaperones discriminate HP1BP3 from canonical H1 not resolved
    • Whether HP1BP3's active-locus preference is functionally required for its miRNA-processing and imprinting roles is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified model explaining how HP1BP3's linker-histone, microprocessor-scaffolding, and imprinting-protection functions are coordinated across genomic loci and cell states remains to be constructed.
  • No genome-wide study simultaneously mapping HP1BP3 chromatin occupancy, microprocessor recruitment, and transcriptional output
  • Post-translational modifications that switch HP1BP3 between its distinct functional modes are uncharacterized
  • Structural basis of HP1BP3–Drosha and HP1BP3–EZH2 interactions not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0005198 structural molecule activity 2 GO:0042393 histone binding 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 6 GO:0005634 nucleus 5
Pathway
R-HSA-4839726 Chromatin organization 6 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1640170 Cell Cycle 1
Partners
DGCR8DROSHAEZH2HP1NPM1PGC7TAF-I
Complex memberships
Drosha–DGCR8 microprocessor

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 HP1BP3 (HP1-BP74) middle region (residues Lys97–Lys274) forms a chromatosome-like structure with reconstituted mononucleosomes, protects ~25 bp of linker DNA from MNase digestion, and its globular domain (Met153–Thr237) adopts a structure similar to the globular domain of linker histones as determined by NMR. Full-length HP1-BP74 and the middle region directly bind HP1 (heterochromatin protein 1), with specific binding sites identified. NMR structure determination, MNase protection assay, in vitro reconstitution with mononucleosomes, direct binding assay to HP1 The Journal of biological chemistry High 20042602
2014 HP1BP3 shows strikingly dynamic association with chromatin during different stages of interphase (quantified by iTRAQ proteomics after partial MNase digestion). Loss-of-function experiments revealed HP1BP3 maintains heterochromatin integrity during G1-S progression and regulates the duration of G1 phase, critically influencing cell proliferative capacity. Partial MNase digestion + iTRAQ quantitative proteomics; biochemical and functional assays including cell cycle analysis Molecular & cellular proteomics : MCP Medium 24830416
2014 HP1BP3 mediates chromatin condensation during hypoxia in tumor cells. Proteomic and functional experiments showed that HP1BP3 promotes chromatin condensation under hypoxic conditions, leading to increased tumor cell viability, radio-resistance, chemo-resistance, and self-renewal. DNase I partial digestion + iTRAQ quantitative proteomics; functional assays for cell viability, radio/chemo-resistance, self-renewal under hypoxia Molecular & cellular proteomics : MCP Medium 25100860
2015 HP1BP3 is evolutionarily and structurally related to histone H1, containing three globular domains and a highly positively charged C-terminal domain. FRAP studies demonstrated that, like H1, chromatin binding of HP1BP3 depends on both its C- and N-terminal regions and is affected by cell cycle stage and post-translational modifications. HP1BP3 contains functional motifs absent from H1, including an acidic stretch and a consensus HP1-binding motif. Transcriptional profiling of HP1BP3-depleted HeLa cells showed altered expression of 383 genes. Hp1bp3−/− mice exhibit 60% neonatal lethality and lifelong ~20% growth retardation. FRAP (live-cell imaging), sequence/structural analysis, transcriptional profiling, knockout mouse model Nucleic acids research High 25662603
2015 HP1BP3 knockout mice are proportionate dwarfs with severely impaired cortical and trabecular bone. Primary osteoblast and osteoclast cultures from Hp1bp3−/− mice showed normal differentiation and function, indicating the growth/bone defect is non-cell-autonomous. At 3 weeks of age, Hp1bp3−/− mice showed a 60% reduction in circulating IGF-1 and a 4-fold increase in IGFBP-1 and IGFBP-2, with corresponding changes in hepatic transcripts of Igf1, Igfbp1, and Igfbp2, placing HP1BP3 upstream of the endocrine IGF-1 axis. Knockout mouse model, microCT bone analysis, primary cell culture differentiation assays, ELISA for circulating IGF-1/IGFBPs, qRT-PCR Endocrinology Medium 26402843
2016 HP1BP3, a histone H1-like chromatin protein, specifically associates with the Drosha-DGCR8 microprocessor complex and promotes global miRNA biogenesis. ChIP studies revealed genome-wide co-localization of HP1BP3 and Drosha at actively transcribed miRNA loci, and HP1BP3 binding is required for Drosha recruitment to these loci. HP1BP3 directly binds endogenous pri-miRNAs and facilitates the Drosha/pri-miRNA association in vivo. Knockdown of HP1BP3 causes premature release of pri-miRNAs from chromatin, compromising co-transcriptional pri-miRNA processing. Co-immunoprecipitation, ChIP-seq, RNA immunoprecipitation, knockdown with miRNA profiling Molecular cell High 27425409
2016 Deletion of Hp1bp3 in mice recapitulates memory deficits characteristic of aged cognitively impaired mice and humans. HP1BP3 protein levels are significantly reduced in hippocampi of cognitively impaired elderly humans relative to cognitively intact controls, supporting a role for HP1BP3-associated molecular networks in modulating cognitive aging. Knockout mouse model with behavioral testing, western blot/quantification in human hippocampal tissue Neurobiology of aging Medium 27460150
2016 Hp1bp3−/− female mice fail to retrieve pups and show reduced anxiety-like behavior in open-field and elevated-plus-maze tests, with pup survival rescued by co-fostering with wild-type dams. Social behavior, depression, motor coordination, olfactory capability, cholinergic status, and brain miRNA profiles were unchanged, indicating a specific role for HP1BP3 in regulating maternal and anxiety-related behavior. Knockout mouse model, pup retrieval test, open-field test, elevated-plus-maze, co-fostering rescue experiment, cholinergic assays, miRNA profiling Genes, brain, and behavior Medium 27470444
2021 HP1BP3 promotes tumor growth and metastasis in esophageal squamous cell carcinoma by upregulating miR-23a, which directly targets the 3′UTR of TRAF5. Knockdown of HP1BP3 inhibited tumor growth and metastasis in vivo, whereas overexpression enhanced these phenotypes; the effect is mechanistically linked to miR-23a-mediated suppression of TRAF5. Knockdown/overexpression with in vivo xenograft models, luciferase 3′UTR reporter assay, miRNA profiling American journal of cancer research Medium 34249436
2022 EZH2 physically interacts with HP1BP3 in glioma stem cells (GSCs), as shown by immunoprecipitation and mass spectrometry. This interaction impairs H3K9 methylation. Overexpression of HP1BP3 enhances GBM cell proliferation, self-renewal, and temozolomide resistance. EZH2 and HP1BP3 co-activate WNT7B expression, and inhibition of WNT7B autocrine signaling with LGK974 reverses TMZ resistance. Co-immunoprecipitation + mass spectrometry, overexpression/knockdown functional assays, transcriptomics, pharmacological inhibition Oncogene Medium 36517590
2024 PGC7 interacts with the central globular domain of HP1BP3 through its C-terminal tail. HP1BP3 recruits PGC7 to the Meg3 differentially methylated region (DMR) in the Dlk1-Dio3 imprinted domain. Depletion of either HP1BP3 or PGC7 decreases their enrichment at the Meg3-DMR, leading to DNA hypermethylation. Cooperative binding of PGC7 and HP1BP3 antagonizes DNMT3A enrichment at the Meg3-DMR, and depletion of either induces chromosome decondensation at this region. Co-immunoprecipitation (domain mapping), ChIP, knockdown with bisulfite sequencing/methylation analysis, DNMT3A ChIP Journal of cellular biochemistry Medium 39422314
2025 HP1BP3 functions as a linker histone variant: it efficiently binds nucleosome core particles (NCPs) with similar efficiency to canonical linker histones, forming a chromatosome, with one HP1BP3 binding per NCP. Its NCP-binding activity is regulated by the linker histone chaperones NPM1 and TAF-I, which interact with the globular domains and C-terminal disordered region of HP1BP3. ChIP-seq demonstrated that HP1BP3 preferentially associates with genomic loci enriched for active histone H3 modification marks, whereas H1.2 prefers inactive loci; these preferences are diminished upon knockdown of NPM1 or TAF-I. Biochemical NCP-binding assays, chromatosome reconstitution, Co-IP for chaperone interactions, ChIP-seq, knockdown Epigenetics & chromatin High 40140990

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of cell biology 1850 22412018
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2016 An improved smaller biotin ligase for BioID proximity labeling. Molecular biology of the cell 665 26912792
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2013 Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS. Nature methods 170 23455922
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2009 Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia. European archives of psychiatry and clinical neuroscience 159 19165527
2012 Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Molecular & cellular proteomics : MCP 145 22586326
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2009 Direct binding of CoREST1 to SUMO-2/3 contributes to gene-specific repression by the LSD1/CoREST1/HDAC complex. Molecular cell 140 19394292
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2014 Profiling of the Chromatin-associated Proteome Identifies HP1BP3 as a Novel Regulator of Cell Cycle Progression. Molecular & cellular proteomics : MCP 43 24830416
2014 Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis. Molecular & cellular proteomics : MCP 38 25100860
2016 Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. Neurobiology of aging 31 27460150
2016 HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing. Molecular cell 29 27425409
2015 HP1BP3 is a novel histone H1 related protein with essential roles in viability and growth. Nucleic acids research 27 25662603
2009 The middle region of an HP1-binding protein, HP1-BP74, associates with linker DNA at the entry/exit site of nucleosomal DNA. The Journal of biological chemistry 22 20042602
2022 EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma. Oncogene 21 36517590
2015 Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway. Endocrinology 14 26402843
2016 HP1BP3 expression determines maternal behavior and offspring survival. Genes, brain, and behavior 11 27470444
2021 HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma. American journal of cancer research 10 34249436
2017 The novel transcriptional factor HP1BP3 negatively regulates Hsp70 transcription in Crassostrea hongkongensis. Scientific reports 5 28469151
2025 Function of HP1BP3 as a linker histone is regulated by linker histone chaperones, NPM1 and TAF-I. Epigenetics & chromatin 1 40140990
2024 Interaction of PGC7 and HP1BP3 Maintains Meg3-DMR Methylation by Regulating Chromatin Configuration. Journal of cellular biochemistry 1 39422314