Affinage

H1-3

Histone H1.3 · UniProt P16402

Length
221 aa
Mass
22.4 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

H1-3 (histone H1.3) is a linker histone variant that compacts chromatin and represses transcription, preferentially occupying the nuclear periphery, high-GC-content chromatin, and H3K27me3-marked repressive domains (PMID:38530350, PMID:42098859). As a purified protein it condenses DNA and binds four-way junction DNA, biochemical activities consistent with its chromatin-organizing role (PMID:9473455). H1.3 enforces the nuclear architecture of the linker histone family: its depletion redistributes other variants—shifting H1.4 and H1.0 toward the periphery and displacing H1.2 into H1.3-vacated regions—thereby altering chromatin and perturbing interferon and cell cycle gene programs (PMID:38530350, PMID:42098859). At a specific locus, H1.3 acts as a repressor of the noncoding oncogene H19, increasing its occupancy at the imprinting control region with concomitant gain of DNA methylation, loss of CTCF, and reduced cell growth (PMID:25205099); its abundance is controlled by HUWE1, which ubiquitinates H1.3 to target it for proteasomal degradation, an axis that gates H19-driven ovarian cancer transformation (PMID:28687618). Beyond chromatin, H1.3 has context-specific roles: during mitosis it assembles with HDAC3, SMRT, and NCoR, targeting CK2-activated HDAC3 deacetylase activity to the spindle apparatus (PMID:26663086), and in antiviral innate immunity it interacts with MAVS and IRF3 to drive IRF3 phosphorylation and nuclear translocation and boost MDA5-dependent IFN-β production, with its N-terminal domain being critical for this signaling (PMID:40580683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1989 High

    Establishing the complete primary structure of human H1.3 defined it as a distinct linker histone variant with conserved globular and divergent terminal regions, the structural basis for variant-specific function.

    Evidence Protein sequencing by chymotryptic and carboxypeptidase digestion of the purified protein

    PMID:2613692

    Open questions at the time
    • Sequence alone does not assign function
    • No structural model of chromatin-bound H1.3
  2. 1998 Medium

    Demonstrating that recombinant H1.3 condenses DNA and binds four-way junction DNA provided the first direct biochemical evidence for its intrinsic chromatin-compacting activity.

    Evidence In vitro DNA condensation and four-way junction binding assays with E. coli-expressed His-tagged rat ortholog

    PMID:9473455

    Open questions at the time
    • Activities shown in vitro, not in chromatin context
    • Single lab, ortholog protein
    • No comparison of variant specificity
  3. 2014 High

    Identifying H1.3 as a locus-specific repressor of the H19 oncogene showed that a linker histone can direct targeted gene silencing coupled to DNA methylation and CTCF displacement, not only global compaction.

    Evidence Reciprocal overexpression/knockdown in OVCAR-3 cells with ChIP, bisulfite sequencing, and growth assays

    PMID:25205099

    Open questions at the time
    • Mechanism of H1.3 recruitment to the ICR unknown
    • Whether other loci are similarly targeted not addressed
  4. 2015 High

    Discovery of a mitotic H1.3–HDAC3–SMRT–NCoR complex activated by CK2 phosphorylation revealed a non-chromatin, cell-cycle-restricted role linking H1.3 to deacetylase targeting at the spindle.

    Evidence Co-IP from synchronized HeLa cells, in vitro CK2 kinase and HDAC activity assays, CK2 knockdown, immunofluorescence co-localization

    PMID:26663086

    Open questions at the time
    • Functional consequence of HDAC3 spindle targeting unresolved
    • Substrates of the mitotic complex not identified
  5. 2017 High

    Showing that HUWE1 ubiquitinates H1.3 for proteasomal degradation placed H1.3 abundance under post-translational control and connected this axis to H19-driven tumor growth.

    Evidence Reciprocal Co-IP, ubiquitination assay, Huwe1 mouse deletion, and H1.3/H19 rescue experiments in ovarian cancer cells

    PMID:28687618

    Open questions at the time
    • Ubiquitination sites on H1.3 not mapped
    • Signals controlling HUWE1–H1.3 interaction unknown
  6. 2022 Medium

    Mapping HDAC1-dependent serine-38 phosphorylation of H1.2/H1.3/H1.4 began to define the PTM landscape regulating linker histone function.

    Evidence HDAC1 knockdown with mass spectrometry PTM profiling of linker histones

    PMID:35743829

    Open questions at the time
    • H1.2 and H1.3 not resolved individually
    • Functional consequence of S38 phosphorylation untested
    • Single lab
  7. 2024 Medium

    Super-resolution imaging established H1.3 as universally enriched at the nuclear periphery and showed it dictates the spatial distribution of other H1 variants, defining a hierarchical organization role at the lamina.

    Evidence Super-resolution immunofluorescence and variant knockdown across multiple human cell lines

    PMID:38530350

    Open questions at the time
    • Molecular basis of peripheral targeting unknown
    • How redistribution affects gene expression not addressed here
  8. 2025 Medium

    Identifying H1.3 interactions with MAVS and IRF3 revealed an unexpected cytoplasmic role in antiviral innate immunity, amplifying MDA5/IFN-β signaling via its N-terminal domain.

    Evidence Endogenous and exogenous Co-IP, gain/loss-of-function and phosphorylation/translocation readouts during EMCV infection in A549 cells

    PMID:40580683

    Open questions at the time
    • Cytoplasmic pool of a nuclear histone not mechanistically explained
    • Direct vs indirect interaction with signaling components unresolved
    • Single lab single study
  9. 2026 High

    Genome-wide mapping in AML cells linked H1.3 occupancy at high-GC/H3K27me3 chromatin to repression, and showed its loss redistributes H1.2 and reprograms interferon and cell cycle genes, unifying its compaction role with downstream transcriptional outputs.

    Evidence ChIP-seq, RNA-seq, and CRISPR knockout with H1.2 redistribution analysis in AML cells

    PMID:42098859

    Open questions at the time
    • Causal chain from H1.2 redistribution to specific gene changes not fully resolved
    • Whether interferon link connects to the MAVS/IRF3 role untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How H1.3 is targeted to specific chromatin domains and individual loci, and how its nuclear chromatin role mechanistically relates to its mitotic and cytoplasmic antiviral functions, remains unresolved.
  • No structural model of locus-specific recruitment
  • Connection between distinct subcellular roles unestablished
  • PTM-to-function map incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-168256 Immune System 1
Partners
CTCFHDAC3HUWE1IRF3MAVSNCOR1SMRT
Complex memberships
HDAC3–SMRT–NCoR complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 Complete amino acid sequence of human histone H1d (H1-3) was determined, establishing it as a 212-residue protein with an acetylated N-terminal serine, showing sequence conservation in the ~70 internal (globular domain) residues but variation in N-terminal and C-terminal regions compared to other H1 variants. Protein sequencing (chymotryptic digestion, carboxypeptidase digestion, N-terminal sequencing) Journal of biochemistry High 2613692
1990 A rat genomic clone encoding histone H1d (H1-3 ortholog) was isolated; in vitro transcription and translation of the gene produced a protein whose electrophoretic mobility matched the H1d variant, confirming gene identity. Genomic cloning, SP6 RNA polymerase transcription, cell-free translation, SDS-PAGE mobility comparison Gene Medium 2373370
1998 Recombinant rat histone H1d (H1-3 ortholog) expressed in E. coli was shown to (a) condense DNA and (b) bind specifically to synthetic four-way junction DNA, establishing these biochemical activities for the purified protein. Recombinant protein expression (pTrc99A, 6-His tag), Ni2+-NTA and heparin-agarose purification, DNA condensation assay, four-way junction DNA binding assay Protein expression and purification Medium 9473455
2003 The rat H1d (H1-3 ortholog) gene contains an intragenic activating region (IAR) at +21 to +116 that confers 2–3-fold upregulation of expression; two Omega elements at +32 and +66 account for the activating effect, and a YY1/alpha-like site overlaps the translational start codon. These elements bind proteins similar to those binding the mouse H3.2 CRAS. Transient transfection reporter assays (NIH3T3 cells), targeted mutagenesis, stepwise deletions, gel-shift (EMSA) assays with transcription factor YY1 Biochimica et biophysica acta Medium 12531475
2009 H1.3 (H1-3) and its C-terminal fragment N.1 (generated by Asp-N endoproteinase cleavage at the single aspartate) selectively inhibit gamma-thrombin-induced platelet aggregation via the PAR-4 receptor; removal of two N-terminal amino acids (Asp-Val) from N.1 further enhanced PAR-4 inhibitory activity. Platelet aggregation assay, proteolytic fragmentation of H1.3, MALDI mass spectrometry for fragment identification Platelets Medium 19637099
2014 H1.3 (H1-3) acts as a specific transcriptional repressor of the noncoding oncogene H19 in ovarian cancer cells: overexpression of H1.3 increases its occupancy at the H19 imprinting control region (ICR), concomitant with increased DNA methylation and reduced CTCF occupancy at the ICR, suppressing H19 expression and decreasing cell growth. H1.3 overexpression and knockdown in OVCAR-3 cells, ChIP (chromatin immunoprecipitation) for H1.3 occupancy at H19 ICR, bisulfite sequencing for DNA methylation, colony formation and growth rate assays Cancer research High 25205099
2015 H1.3 (H1-3) forms a novel complex with HDAC3, SMRT, and NCoR that accumulates in late G2 and mitosis in HeLa cells; HDAC3 deacetylase activity in this complex is activated only during mitosis upon phosphorylation of HDAC3 at Ser-424 by protein kinase CK2. H1.3 and HDAC3 co-localize between chromosomes, with polar microtubules and spindle poles during metaphase through telophase, suggesting H1.3 targets HDAC3 to microtubules. Co-immunoprecipitation from synchronized HeLa cells, in vitro kinase assay (CK2 phosphorylation of HDAC3 in isolated complexes), HDAC activity assay, CK2α/CK2α' double knockdown, immunofluorescence co-localization The Journal of biological chemistry High 26663086
2017 HUWE1 E3 ubiquitin ligase binds and ubiquitinates H1.3 (H1-3), targeting it for proteasomal degradation; loss of HUWE1 increases H1.3 protein levels, which in turn represses H19 noncoding RNA expression, inhibiting ovarian cancer cell transformation and tumor growth. Co-immunoprecipitation (HUWE1–H1.3 interaction), ubiquitination assay, Huwe1 genetic deletion in mouse, inducible HUWE1 silencing in human ovarian cancer cells, H1.3 and H19 knockdown rescue experiments Cancer research High 28687618
2022 HDAC1 depletion specifically potentiates phosphorylation of H1.2/H1.3 (H1-3) and H1.4 at serine 38, without changing H1 acetylation levels, as revealed by mass spectrometry analysis of post-translational modifications. HDAC1 knockdown, mass spectrometry-based PTM analysis of linker histones Life (Basel, Switzerland) Medium 35743829
2024 H1.3 (H1-3) is universally enriched at the nuclear periphery and co-localizes with compacted DNA across all human cell lines examined; depletion of H1.3 causes H1.4 and H1.0 to shift toward a more peripheral distribution, indicating H1.3 influences the nuclear distribution of other H1 variants and contributes to chromatin compaction at the lamina. Immunofluorescence imaging including super-resolution microscopy, H1 variant knockdown, quantitative distribution analysis across multiple human cell lines eLife Medium 38530350
2025 H1.3 (H1-3) interacts with MAVS and IRF3 (confirmed by endogenous and exogenous Co-IP), promotes IRF3 phosphorylation and nuclear translocation, upregulates MDA5 expression, and enhances TBK1 and IRF3 phosphorylation during EMCV infection to boost IFN-β production. The N-terminal domain of H1.3 is identified as critical for regulating the IFN-β signaling pathway. Additionally, EMCV infection increases phosphorylation of H1.3 itself. H1.3 overexpression and knockdown in A549 cells, endogenous and exogenous Co-immunoprecipitation (H1.3–MAVS and H1.3–IRF3), immunoblotting for TBK1/IRF3 phosphorylation, nuclear fractionation for IRF3 translocation, N-terminal domain deletion analysis, viral replication assay Molecular immunology Medium 40580683
2026 In AML cells, H1.3 (H1-3) is enriched in high-GC-content chromatin regions and co-localizes with repressive H3K27me3 mark, consistent with a role in chromatin compaction and transcriptional repression. Knockout of H1.3 causes H1.2 to redistribute from its normal chromatin regions to H1.3-occupied regions, leading to chromatin alterations and changes in interferon-related signaling and cell cycle gene programs. ChIP-seq chromatin mapping, transcriptomic analysis (RNA-seq), H1.3 CRISPR knockout in AML cells, H1.2 ChIP-seq redistribution analysis Epigenetics & chromatin High 42098859

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Histone h1.3 suppresses h19 noncoding RNA expression and cell growth of ovarian cancer cells. Cancer research 71 25205099
1989 Human spleen histone H1. Isolation and amino acid sequences of three minor variants, H1a, H1c, and H1d. Journal of biochemistry 51 2613692
2017 Variant SNPs at the microRNA complementary site in the B7‑H1 3'‑untranslated region increase the risk of non‑small cell lung cancer. Molecular medicine reports 43 28677815
2017 Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade. Cancer research 37 28687618
1990 Isolation of a genomic clone encoding the rat histone variant, H1d. Gene 30 2373370
1996 Chromosome mapping of rat histone genes H1fv, H1d, H1t, Th2a and Th2b. Cytogenetics and cell genetics 13 9040779
2015 Mitotic Activation of a Novel Histone Deacetylase 3-Linker Histone H1.3 Protein Complex by Protein Kinase CK2. The Journal of biological chemistry 12 26663086
1993 A rat histone H2B pseudogene is closely associated with the histone H1d gene. Biochimica et biophysica acta 12 8439560
1991 Purification and partial sequencing of inhibitory factor on renal membrane adenylate cyclase in pancreatic cancer extract: identity with histones H1b or H1d. Biochemical and biophysical research communications 10 2018521
1998 Expression of rat histone H1d in Escherichia coli and its purification. Protein expression and purification 9 9473455
2024 Imaging analysis of six human histone H1 variants reveals universal enrichment of H1.2, H1.3, and H1.5 at the nuclear periphery and nucleolar H1X presence. eLife 5 38530350
2022 The Highest Density of Phosphorylated Histone H1 Appeared in Prophase and Prometaphase in Parallel with Reduced H3K9me3, and HDAC1 Depletion Increased H1.2/H1.3 and H1.4 Serine 38 Phosphorylation. Life (Basel, Switzerland) 4 35743829
2009 Inhibition of gamma-thrombin-induced human platelet aggregation by histone H1subtypes and H1.3 fragments. Platelets 2 19637099
2003 The rat histone H1d gene has intragenic activating sequences that are absent from the testis-specific variant H1t. Biochimica et biophysica acta 2 12531475
2026 H1.3 depletion in AML cells prompts H1.2 redistribution, chromatin remodeling and cell cycle defects. Epigenetics & chromatin 0 42098859
2025 Linker histone H1.3 promotes IFN-β production targeting MDA5 signaling to inhibit EMCV infection. Molecular immunology 0 40580683

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