Affinage

HIRA

Protein HIRA · UniProt P54198

Length
1017 aa
Mass
111.8 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIRA is a histone H3.3 chaperone that functions as a homotrimeric scaffold within the quaternary HIRA/UBN1/CABIN1/ASF1a (HUCA) complex to mediate DNA replication-independent nucleosome assembly at active promoters, enhancers, gene bodies, and sites of DNA damage (PMID:12049744, PMID:23602572, PMID:30082790). UBN1 provides H3.3 specificity through recognition of residues Ala87/Gly90, while RPA recruits the complex to chromatin; HIRA mediates two distinct H3.3 pathways during transcription—de novo deposition requiring trimerization and UBN1, and old histone recycling requiring ASF1a interaction—and cooperates with the SRCAP complex to co-deposit H3.3 and H2A.Z at poised promoters (PMID:30285846, PMID:28107649, PMID:32895554, PMID:34893908). HIRA is essential for paternal chromatin assembly at fertilization, maintenance of chromatin integrity and transcriptional identity in non-proliferating cells including oocytes and muscle stem cells, senescence-associated heterochromatin foci (SAHF) formation via PML body transit, restriction of herpesvirus gene expression through chromatinization of viral DNA, and transcription recovery after UV damage partly by relieving ATF3-mediated repression rather than solely through local H3.3 deposition (PMID:16251970, PMID:26549683, PMID:34103504, PMID:15621527, PMID:28981850, PMID:34158510). Its activity is regulated by cyclin A/E-cdk2 phosphorylation at Thr555 in S phase and by OGT-mediated O-GlcNAcylation at Ser231, which promotes H3.3 complex formation and senescence (PMID:11238922, PMID:27217568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Establishing that HIRA is cell-cycle regulated: the discovery that cyclin A/E-cdk2 phosphorylates HIRA at Thr555 in S phase, and that ectopic HIRA causes S-phase arrest, placed HIRA under direct cell-cycle kinase control and suggested its activity is normally restricted outside S phase.

    Evidence In vitro kinase assay with RXL-mutant analysis, in vivo phosphorylation mapping, p21 inhibition, cell cycle analysis in human cells

    PMID:11238922

    Open questions at the time
    • Functional consequence of Thr555 phosphorylation on nucleosome assembly not determined
    • Whether cdk2 phosphorylation is inhibitory or activating for H3.3 deposition unclear
  2. 2002 High

    Defining HIRA as a replication-independent nucleosome assembly factor: immunodepletion from Xenopus egg extracts abolished nucleosome assembly on non-replicated DNA while leaving replication-coupled assembly intact, establishing the fundamental biochemical activity of HIRA.

    Evidence In vitro reconstitution with recombinant Xenopus HIRA, immunodepletion/rescue in Xenopus egg extracts

    PMID:12049744

    Open questions at the time
    • Histone variant specificity (H3.3 vs. H3.1) not yet established in this system
    • In vivo genomic targets unknown
  3. 2002 High

    Demonstrating in vivo essentiality: targeted disruption of Hira in mice causes early embryonic lethality with gastrulation defects, proving HIRA is indispensable for mammalian development.

    Evidence Gene knockout in mouse with embryological phenotypic analysis

    PMID:11884616

    Open questions at the time
    • Molecular basis of gastrulation defects (chromatin vs. transcriptional vs. signaling) not resolved
    • Cell-type-specific requirements unknown
  4. 2005 High

    Linking HIRA to cellular senescence and H3.3 variant specificity: HIRA transits through PML bodies and, with ASF1a, is rate-limiting for SAHF formation; independently, Drosophila HIRA was shown to specifically deposit H3.3 (not H3) onto paternal chromatin at fertilization, establishing histone variant selectivity.

    Evidence Co-IP, immunofluorescence, dominant-negative epistasis in senescent human cells; genetic loss-of-function in Drosophila with H3.3 vs. H3 immunostaining

    PMID:15621527 PMID:16251970

    Open questions at the time
    • Mechanism of H3.3 selectivity at the molecular level unknown
    • Whether SAHF formation requires H3.3 deposition or another HIRA function unclear
  5. 2006 High

    Revealing the structural basis of the HIRA-ASF1a interaction: crystal structure showed HIRA B domain binds ASF1a via a beta-hairpin, and CAF-1 p60 competes for the same ASF1a surface, explaining mutual exclusivity of replication-independent and replication-coupled assembly pathways.

    Evidence X-ray crystallography of human ASF1a–HIRA B domain, competition binding assays, mutagenesis

    PMID:16980972

    Open questions at the time
    • Structure of full-length HIRA or HUCA complex not determined
    • How competition is regulated in vivo unknown
  6. 2008 High

    Identifying UBN1 as an essential HIRA complex subunit: UBN1 binds HIRA WD repeats via its conserved HRD domain, is required for SAHF formation, and associates with H3K9 methyltransferase activity, expanding the complex beyond a HIRA-ASF1a dimer.

    Evidence Co-IP, pulldown assays, shRNA knockdown with SAHF readout, histone methyltransferase assay in human cells

    PMID:19029251

    Open questions at the time
    • Whether UBN1 directly contacts H3.3 not yet tested
    • Identity of associated H3K9 methyltransferase not established
  7. 2011 High

    Reconstituting the quaternary HUCA complex: recombinant HIRA, UBN1, CABIN1, and ASF1a form a stable quaternary complex with HIRA as scaffold; CABIN1 is required for heterochromatinization in senescence, completing the core complex architecture.

    Evidence Recombinant complex reconstitution, co-IP, shRNA knockdown with SAHF readout, ChIP in human cells

    PMID:21807893

    Open questions at the time
    • Stoichiometry of the complex not fully defined
    • How CABIN1 contributes biochemically to nucleosome assembly unclear
  8. 2013 High

    Mapping the genome-wide occupancy of HIRA: ChIP-seq revealed HIRA/UBN1/ASF1a colocalize with H3.3 predominantly at active promoters and enhancers, and HIRA interacts with transcription factors and chromatin remodelers, defining the genomic landscape of HIRA-mediated H3.3 deposition.

    Evidence ChIP-seq for HIRA, UBN1, ASF1a, H3.3 in human cells; co-IP of interacting partners

    PMID:23602572

    Open questions at the time
    • Mechanism of HIRA recruitment to specific regulatory elements unknown
    • Contribution of individual interactors to targeting not dissected
  9. 2015 High

    Establishing HIRA as essential for chromatin integrity in non-dividing cells: conditional deletion in mouse oocytes caused increased chromatin accessibility, DNA damage, spurious transcription, and defective DNA methylation, showing continuous H3.3 deposition maintains genome organization in quiescent cells.

    Evidence Conditional oocyte-specific knockout, SNAP-tag pulse-chase, DNase I sensitivity, RNA-seq, bisulfite sequencing

    PMID:26549683

    Open questions at the time
    • Whether chromatin defects are solely due to loss of H3.3 or also loss of histone recycling unclear
    • Relevance to other quiescent cell types not established
  10. 2016 High

    Identifying O-GlcNAcylation as a regulatory modification: OGT modifies HIRA at Ser231, promoting HIRA-H3.3 complex formation and H3.3 nucleosome assembly; a S231A mutant impairs assembly and delays senescence, linking metabolic signaling to chromatin dynamics.

    Evidence Co-IP, O-GlcNAcylation site mapping, HIRA S231A mutant functional assay, nucleosome assembly assay, senescence assay in human cells

    PMID:27217568

    Open questions at the time
    • How O-GlcNAcylation structurally alters HIRA-H3.3 binding not determined
    • Interplay between OGT modification and cdk2 phosphorylation unexplored
  11. 2017 High

    Identifying RPA as the chromatin-targeting factor for HIRA: RPA physically interacts with HIRA and forms RPA-HIRA-H3.3 complexes; RPA depletion dramatically reduces HIRA chromatin association and new H3.3 deposition at promoters and enhancers, solving the long-standing question of how HIRA is recruited to its genomic targets.

    Evidence shRNA screen, co-IP, ChIP-seq for HIRA/H3.3 after RPA1 depletion, pulse-chase H3.3 assay in human cells

    PMID:28107649

    Open questions at the time
    • Whether RPA recruits HIRA through ssDNA intermediates at promoters not shown
    • Structural basis of RPA-HIRA interaction unknown
  12. 2017 High

    Expanding HIRA function to antiviral defense: HIRA deposits H3.3 onto incoming herpesvirus DNA, relocalizes to PML bodies upon infection, and restricts viral gene expression; HIRA also promotes innate immune gene transcription at ISGs in a PML-dependent manner.

    Evidence ChIP on viral DNA, immunofluorescence, HIRA KO with viral replication readouts in vitro and in vivo (murine CMV); RNA-seq and ChIP-seq at ISGs

    PMID:28981850 PMID:30901352

    Open questions at the time
    • Whether chromatinization of viral DNA is sufficient for restriction or whether transcriptional activation of ISGs is the primary mechanism is unresolved
    • Viral countermeasures beyond ICP0 not characterized
  13. 2018 High

    Determining HIRA homotrimerization as functionally essential: crystal structure revealed HIRA forms a homotrimer (structurally related to Ctf4/AND-1) that binds two CABIN1 subunits; trimerization-deficient mutants fail to deposit H3.3 and cannot localize to UV-damage sites.

    Evidence X-ray crystallography of HIRA trimerization domain, mutagenesis, ChIP after UV, complementation in HIRA-KO cells

    PMID:30082790

    Open questions at the time
    • Complete structure of the assembled HUCA complex not available
    • How trimeric architecture interfaces with RPA recruitment unknown
  14. 2018 High

    Pinpointing UBN1 as the H3.3-specificity subunit: UBN1 directly binds H3.3 via Ala87/Gly90; HIRA enhances this binding; UBN1 and UBN2 define two cooperating HIRA complexes that together deposit H3.3 at active regulatory elements.

    Evidence In vitro binding assays with H3.3 mutants (A87/G90), ChIP-seq in UBN1/2 mutant mES cells, differentiation assays

    PMID:30285846

    Open questions at the time
    • Structural basis of UBN1-H3.3 recognition not determined at atomic resolution
    • Division of labor between UBN1-HIRA and UBN2-HIRA complexes at specific loci unclear
  15. 2020 High

    Dissecting two mechanistically distinct H3.3 deposition pathways: de novo H3.3 deposition requires HIRA trimerization and UBN1 but not ASF1a interaction, while recycling of old H3.3 requires ASF1a but not UBN1 or trimerization, revealing that HIRA coordinates parallel chromatin maintenance mechanisms.

    Evidence SNAP-tag pulse-chase distinguishing new/old histones, structure-guided HIRA domain mutants, ChIP in human cells

    PMID:32895554

    Open questions at the time
    • How the two pathways are coordinated at a single locus unknown
    • Whether recycling pathway involves parental H3.3-associated modifications is untested
  16. 2021 High

    Revealing HIRA's role in transcription recovery after UV damage is largely independent of local H3.3 deposition: HIRA is recruited to UV sites via VCP, but genome-wide transcription restart depends on HIRA stabilizing UBN2 and reducing ATF3 repressor expression, separating chromatin restoration from transcription recovery functions.

    Evidence HIRA KO, nascent RNA-seq (Bru-seq), ChIP at UV-damaged sites, VCP inhibition, ATF3/UBN2 epistasis in human cells

    PMID:34158510

    Open questions at the time
    • Mechanism by which HIRA suppresses ATF3 expression not determined
    • Whether the VCP-dependent and VCP-independent pathways converge unclear
  17. 2021 High

    Demonstrating HIRA maintains lineage fidelity in adult stem cells: conditional ablation in muscle stem cells reduces H3.3 and H3K27ac at muscle gene regulatory regions and causes ectopic expression of alternative lineage genes via MLL1/MLL2-mediated H3K4me3 gain, showing HIRA prevents aberrant chromatin states during tissue regeneration.

    Evidence Muscle-specific conditional KO, ATAC-seq, ChIP-seq for H3.3/H3K4me3/H3K27ac, RNA-seq, in vivo regeneration assay

    PMID:34103504

    Open questions at the time
    • Whether HIRA loss directly causes MLL1/MLL2 recruitment or this is an indirect consequence is unclear
    • Whether similar lineage infidelity occurs in other adult stem cell types untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the complete atomic structure of the assembled HUCA homotrimeric complex with bound H3.3-H4; the mechanism by which RPA recognizes and recruits HIRA to specific genomic loci; how the de novo deposition and old histone recycling pathways are coordinated at individual nucleosomes; and whether the transcription-recovery function of HIRA (via ATF3/UBN2) operates through a chaperone-independent mechanism.
  • No complete cryo-EM or crystal structure of the full HUCA-H3.3-H4 complex
  • Structural basis of RPA-HIRA interaction undetermined
  • Chaperone-independent functions of HIRA not mechanistically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 5 GO:0044183 protein folding chaperone 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 5 GO:0000228 nuclear chromosome 4 GO:0005694 chromosome 3
Pathway
R-HSA-4839726 Chromatin organization 9 R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1640170 Cell Cycle 4 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2
Partners
ASF1ACABIN1OGTPHBRPA1UBN1UBN2WHSC1
Complex memberships
HIRA homotrimerHIRA/UBN1/CABIN1/ASF1a (HUCA) complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 HIRA promotes nucleosome assembly on non-replicated DNA in a DNA synthesis-independent manner; recombinant Xenopus HIRA bound purified core histones and promoted their deposition onto plasmid DNA, and immunodepletion of HIRA from Xenopus egg extracts severely impaired nucleosome assembly on non-replicated DNA while leaving replication-coupled assembly intact; defect was rescued by reintroduction of HIRA with (H3-H4)2 tetramers. In vitro histone-binding assay, immunodepletion of Xenopus egg extracts, nucleosome assembly assay on non-replicated vs. replicated DNA, reconstitution rescue Molecular cell High 12049744
2005 HIRA enters PML nuclear bodies as cells approach senescence, where it transiently colocalizes with HP1 proteins prior to HP1 incorporation into SAHF; a physical complex of HIRA and ASF1a is rate-limiting for formation of macroH2A-containing SAHF and onset of senescence-associated cell cycle exit. Immunofluorescence localization, co-immunoprecipitation (HIRA-ASF1a complex), dominant-negative HIRA expression, epistasis analysis of SAHF formation and cell cycle exit Developmental cell High 15621527
2005 Drosophila HIRA (sésame gene product) is required for replication-independent nucleosome assembly on paternal DNA at fertilization, specifically incorporating H3.3 (not H3) into paternal chromatin before the first round of DNA replication, establishing an epigenetic distinction between parental genomes. Genetic loss-of-function (sésame point mutant), immunostaining for H3.3 vs. H3 in paternal chromatin, genetic complementation Nature High 16251970
2006 Crystal structure of the human ASF1a–HIRA heterodimer revealed that the HIRA B domain forms an antiparallel beta-hairpin that binds perpendicular to the beta-sandwich of ASF1a via beta-sheet, salt bridge, and van der Waals contacts; CAF-1 p60 uses B domain-like motifs to compete with HIRA for ASF1a binding; N- and C-terminal regions of ASF1a/ASF1b determine differential affinities for HIRA. X-ray crystallography, biochemical binding/competition assays, mutagenesis Nature structural & molecular biology High 16980972
2007 HIRA's localization to PML bodies is required for SAHF formation: dominant-negative HIRA mutants blocking PML body localization prevent SAHF; PML-RARα disruption of PML bodies also prevents SAHF; HIRA/ASF1a pathway acts in parallel with pRB pathway downstream of PML body localization, converging through DNAJ-domain protein DNAJA2; HIRA translocation to PML bodies occurs independently of functional pRB and p53. Dominant-negative mutant expression, genetic epistasis (pRB/p53 pathway), co-immunoprecipitation (HIRA-DNAJA2), immunofluorescence Molecular and cellular biology High 17242198
2001 Human HIRA is a substrate of cyclin A- and E-cdk2 kinase: HIRA binds cyclin A/E-cdk2 via an RXL motif and is phosphorylated in vitro in an RXL-dependent manner; phosphorylation in vivo on Thr555 by cyclin A-cdk2 occurs in S phase; p21(cip1) blocks this phosphorylation; ectopic HIRA expression causes S-phase arrest. In vitro kinase assay, in vivo phosphorylation mapping, RXL-mutant analysis, p21 inhibition, cell cycle analysis of HIRA-overexpressing cells Molecular and cellular biology High 11238922
2002 Targeted disruption of Hira in mice results in early embryonic lethality with gastrulation defects and malformations of axial and paraxial mesendoderm, demonstrating that Hira is essential for murine embryogenesis. Targeted gene knockout, embryological phenotypic analysis Molecular and cellular biology High 11884616
2007 Drosophila HIRA is essential for assembly of H3.3-containing nucleosomes on the decondensing male pronucleus; protamine removal and histone H3.3 deposition are two functionally distinct processes; HIRA-dependent H3.3 deposition in the male pronucleus does not require ASF1. Loss-of-function allele by homologous recombination, immunostaining for H3.3 and protamines, genetic epistasis with ASF1 PLoS genetics High 17967064
2008 Human UBN1 (ortholog of yeast Hpc2p) directly interacts with the N-terminal WD repeats of HIRA through its evolutionarily conserved Hpc2-related domain (HRD); UBN1 is indispensable for SAHF formation and associates with H3K9 methyltransferase activity at proliferation-promoting genes repressed in senescence. Co-immunoprecipitation, pulldown assays, shRNA knockdown with SAHF phenotype readout, histone methyltransferase assay Molecular and cellular biology High 19029251
2011 Human CABIN1 is a functional member of the quaternary HIRA/UBN1/CABIN1/ASF1a (HUCA) complex assembled from recombinant proteins; HIRA acts as a scaffold to bring UBN1, ASF1a, and CABIN1 together; CABIN1 is required for heterochromatinization in senescent cells and regulates overlapping gene sets with HIRA enriched in H3.3. Recombinant complex reconstitution, co-immunoprecipitation (endogenous and ectopic), mutational analysis, shRNA knockdown with SAHF readout, ChIP Molecular and cellular biology High 21807893
2013 The HIRA chaperone complex (HIRA, UBN1, ASF1a) colocalizes with histone H3.3 predominantly at active promoters and enhancers; HIRA is required for deposition of H3.3 at these sites; HIRA complex physically interacts with transcription factors, a chromatin insulator protein, and an ATP-dependent chromatin-remodeling complex at functionally distinct regulatory sites. ChIP-seq of HIRA, UBN1, ASF1a, H3.3; gene expression analysis; co-immunoprecipitation of HIRA with interacting partners Cell reports High 23602572
2014 HIRA deposits newly synthesized histone H3.3 and H4 into chromatin of nonproliferating senescent cells (replication-independent); HIRA and newly deposited H3.3 colocalize at promoters of expressed genes; HIRA is required for retention of H4K16ac at active gene promoters in senescent cells and in vivo, and is required for suppression of oncogene-induced neoplasia. Pulse-chase histone incorporation assay, ChIP-seq, HIRA knockout/knockdown with tumor suppression assay in vivo Genes & development High 25512559
2015 Conditional deletion of Hira in mouse oocytes demonstrates that continuous H3.3/H4 deposition by HIRA is required for chromatin integrity in non-replicating oocytes; loss of HIRA causes increased DNase I sensitivity, DNA damage accumulation, reduced dynamic range of gene expression, spurious transcripts, and inefficient de novo DNA methylation. Conditional knockout (oocyte-specific Cre), SNAP-tag pulse-chase for histone dynamics, DNase I sensitivity, RNA-seq, bisulfite sequencing Molecular cell High 26549683
2012 The N-terminal domain of UBN1 (residues 41–77, termed NHRD) is essential for interaction with the HIRA WD repeat domain forming a tight 1:1 complex (nanomolar Kd); mutations in NHRD disrupt HUCA complex stability in vitro and in vivo and impair chromatin reorganization in primary human cells. Analytical ultracentrifugation, mutagenesis, in vitro binding assays, co-immunoprecipitation in cells Biochemistry High 22401310
2018 HIRA forms a stable homotrimer that binds two CABIN1 subunits; a HIRA mutant defective in homotrimerization interacts less efficiently with CABIN1, fails to enrich at UV-damage sites, and cannot rescue new H3.3 deposition in HIRA-knockout cells; structural homology to homotrimeric Ctf4/AND-1 replisome component was identified. Biochemical analysis, X-ray crystallography of HIRA trimer domain, mutagenesis of trimerization interface, ChIP after UV, complementation assay in HIRA-KO cells Nature communications High 30082790
2017 RPA (replication protein A) physically interacts with HIRA to form RPA-HIRA-H3.3 complexes; RPA co-localizes with HIRA and H3.3 at gene promoters and enhancers; depletion of RPA1 dramatically reduces HIRA chromatin association and deposition of newly synthesized H3.3 at promoters and enhancers. shRNA screen, co-immunoprecipitation, ChIP-seq for HIRA/H3.3 after RPA1 depletion, pulse-chase H3.3 deposition assay Molecular cell High 28107649
2013 WHSC1 (NSD2/MMSET) associates with HIRA and co-occupies IFN-stimulated genes to support prolonged H3.3 incorporation during transcriptional activation; in Whsc1-/- cells, IFN- or UV-triggered H3.3 deposition is absent and induced transcription is markedly reduced; WHSC1 also links transcriptional elongation (via BRD4/P-TEFb) to HIRA-mediated H3.3 deposition through two molecularly distinct pathways. Co-immunoprecipitation (WHSC1-HIRA), ChIP for H3.3 in Whsc1 KO cells, nascent RNA analysis, genetic epistasis The EMBO journal High 23921552
2016 O-GlcNAc transferase (OGT) interacts with UBN1 and modifies HIRA at Ser231 (O-GlcNAcylation); this modification promotes HIRA-H3.3 complex formation and H3.3 nucleosome assembly; HIRA S231A O-GlcNAcylation-deficient mutant compromises H3.3 assembly and delays premature cellular senescence; OGT overexpression accelerates senescence. Co-immunoprecipitation (OGT-UBN1, OGT-HIRA), O-GlcNAcylation site mapping, HIRA S231A mutant functional assay, H3.3 nucleosome assembly assay, senescence assay Proceedings of the National Academy of Sciences of the United States of America High 27217568
2017 HIRA deposits histone H3.3 onto incoming herpesvirus (HSV, CMV) and transfected plasmid DNA in the nucleus; after infection, HIRA re-localizes to PML bodies, co-localizes with viral genomes, and is required for suppression of viral gene expression and lytic replication; HIRA is also required to restrict murine CMV in vivo. ChIP on viral DNA, immunofluorescence co-localization, HIRA knockdown/knockout with viral gene expression and replication readouts, in vivo murine CMV infection model Nucleic acids research High 28981850
2020 HIRA mediates two distinct H3.3 deposition pathways during transcription: (1) de novo H3.3 deposition requiring HIRA trimerization and UBN1 (ASF1-HIRA interaction dispensable); (2) recycling of old H3.3 requiring HIRA-ASF1 interaction but independent of UBN1 and HIRA trimerization. SNAP-tag system to distinguish new/old histones, HIRA domain mutants (trimerization-deficient, ASF1-binding-deficient, UBN1-interacting-deficient), ChIP in human cells Nature structural & molecular biology High 32895554
2016 Nucleosome disassembly at DNA double-strand breaks during non-homologous end joining is promoted by ATM and INO80; chromatin reassembly after DSB repair requires HIRA (for H3.3, replication-independent) and CAF-1 (for H3.1/H3.2, replication-dependent) acting concertedly and interdependently. Inducible DSB system in human cells, histone H3 ChIP after break induction, HIRA/CAF-1 knockdown with chromatin reassembly readout, epistasis between pathways eLife High 27269284
2013 In Drosophila, Yemanuclein (YEM), the Drosophila Hpc2/Ubinuclein ortholog, interacts physically with HIRA and both proteins are mutually dependent for targeting to the decondensing male pronucleus; HIRA/YEM complex is specifically required for H3.3 deposition in the male pronucleus, with the alternative ATRX/XNP pathway not involved in paternal chromatin assembly. Co-immunoprecipitation (HIRA-YEM), genetic loss-of-function of yem, immunostaining of H3.3 in male pronucleus, genetic epistasis with ATRX/XNP pathway PLoS genetics High 23408912
2018 UBN1 (and UBN2) are the subunits of the HIRA complex primarily responsible for specific recognition and direct binding of H3.3; Ala87 and Gly90 of H3.3 are required and sufficient for UBN1 binding; HIRA enhances UBN1 binding affinity toward H3.3; two HIRA complexes (UBN1-HIRA and UBN2-HIRA) cooperatively deposit H3.3 at active promoters and enhancers; FID/AAA mutation disrupting UBN1/2 chaperone activity impairs H3.3 deposition and neural differentiation gene activation. In vitro binding assays, mutagenesis of H3.3 (A87/G90), ChIP-seq of H3.3 in UBN1/2 mutant mES cells, differentiation assays BMC biology High 30285846
2016 PHB (prohibitin) forms a protein complex with HIRA in human ESCs, stabilizes protein levels of HIRA complex components, and together with HIRA controls global H3.3 deposition; PHB and HIRA regulate chromatin architecture at isocitrate dehydrogenase gene promoters to promote transcription and α-ketoglutarate production, linking epigenetic organization to metabolic regulation. Co-immunoprecipitation (PHB-HIRA), siRNA knockdown, genome-wide H3.3 ChIP, ChIP at IDH gene promoters, metabolite measurement Cell stem cell Medium 27939217
2009 In fission yeast, the HIRA histone chaperone complex is required for promoter silencing, suppression of cryptic antisense transcripts from gene bodies, and silencing of Tf2 retrotransposon LTRs; loss of HIRA increases chromosomal susceptibility to double-strand break-inducing agents, indicating HIRA restricts genomic accessibility. Microarray expression analysis, genetic loss-of-function (deletion of fission yeast Hira genes), sensitivity assays to genotoxic agents Molecular and cellular biology Medium 19620282
2017 HIRA promotes transcriptional upregulation of a broad repertoire of innate immune genes in response to HSV-1 infection, including ISGs, MHC-I antigen presentation, and cytokine signaling genes; PML is required for enrichment of HIRA onto ISGs; HSV-1 ubiquitin ligase ICP0 antagonizes HIRA recruitment to viral genomes and PML-NBs. RNA-seq (HIRA knockdown), ChIP-seq for HIRA at ISGs, immunofluorescence, co-localization with viral genomes PLoS pathogens Medium 30901352
2016 Conditional ablation of Hira in cardiogenic mesoderm causes ventricular/atrial septal defects and embryonic lethality; HIRA binds GAGA-rich DNA at cardiac gene regulatory elements (including TTe enhancer of Tnni2/Tnnt3 bound by NKX2.5) and HIRA-dependent H3.3 enrichment at TTe is observed during ESC differentiation to cardiomyocytes. Conditional cardiac-specific Hira knockout, RNA-seq, ChIP for H3.3 and HIRA at cardiac enhancers, in vitro ESC cardiomyocyte differentiation PloS one Medium 27518902
2017 HIRA cooperates with Setd1A (H3K4 trimethyltransferase) to increase H3K4me3 levels at the β-catenin promoter, enhancing its transcription; HIRA knockdown in neural progenitors reduces β-catenin expression, reduces proliferation, and causes premature neuronal differentiation; overexpression of HIRA, HIRA N-terminal domain, or β-catenin rescues the neurogenesis defects. shRNA knockdown of HIRA in neural progenitors, ChIP for H3K4me3, co-immunoprecipitation (HIRA-Setd1A), rescue by overexpression The Journal of cell biology Medium 28515277
2021 Conditional ablation of HIRA in myogenic cells leads to significant reduction of H3.3 deposition and H3K27ac at muscle gene regulatory regions; Hira-deficient muscle stem cells fail to regenerate and self-renew; alternative lineage genes are ectopically expressed via MLL1/MLL2-mediated H3K4me3 gain at silent promoters. Conditional KO (muscle-specific), ATAC-seq, ChIP-seq for H3.3 and H3K4me3/H3K27ac, RNA-seq, in vivo muscle injury/regeneration assay Nature communications High 34103504
2021 HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3; however, this local H3.3 deposition is dispensable for transcription recovery post-UV; instead, HIRA has a genome-wide role in transcription restart independent of new H3.3, coordinating with ASF1B via two independent pathways: stabilizing UBN2 and reducing expression of transcription repressor ATF3. HIRA knockout/knockdown, nascent RNA-seq (Bru-seq), ChIP for HIRA at UV-damaged sites, VCP inhibition, ATF3 expression analysis, UBN2 stability assay Nature communications High 34158510
2022 HIRA complex interacts physically with the SRCAP complex (H2A.Z chaperone) through the HIRA subunit; HIRA complex depletion causes significant decreases in H2A.Z enrichment genome-wide; HIRA and SRCAP cooperatively deposit H3.3 and H2A.Z at promoters to preset chromatin for poised transcription in mESCs. Co-immunoprecipitation (HIRA-SRCAP), CUT&Tag for H2A.Z and H3.3 in HIRA complex KO cells, ATAC-seq, transcription analysis Nucleic acids research Medium 34893908
2015 HIRA directly interacts with RUNX1; HIRA-mediated incorporation of histone H3.3 at the intronic enhancer (+24 conserved noncoding element) of Runx1 is required for Runx1 expression during endothelial-to-hematopoietic transition; loss of HIRA represses this chromatin element and impairs hematopoietic stem cell generation. Co-immunoprecipitation (HIRA-RUNX1), ChIP for H3.3 at Runx1 +24 enhancer, HIRA knockdown in differentiating mouse ESCs with RUNX1 expression and hematopoietic differentiation readouts The Journal of biological chemistry Medium 25847244
2011 HIRA (but not ASF1a) is required for HP1-mediated formation of ALT-associated PML bodies (APBs) in ALT cancer cells; HIRA and ASF1a colocalize inside PML bodies in normal fibroblasts approaching senescence; knockdown of HIRA reduces p53-mediated induction of large APBs and large HP1 foci, revealing an ASF1a-independent function for HIRA in HP1 localization to PML bodies. shRNA knockdown of HIRA vs. ASF1a, immunofluorescence for APBs and HP1 foci, co-localization studies PloS one Medium 21347226

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Developmental cell 554 15621527
1997 Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science (New York, N.Y.) 444 9204892
1996 Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes & development 412 8675011
1995 Repression by SSN6-TUP1 is directed by MIG1, a repressor/activator protein. Proceedings of the National Academy of Sciences of the United States of America 336 7724528
2002 HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis. Molecular cell 334 12049744
1994 Functional dissection of the yeast Cyc8-Tup1 transcriptional co-repressor complex. Nature 301 8008070
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