Affinage

H1-2

Histone H1.2 · UniProt P16403

Length
213 aa
Mass
21.4 kDa
Annotated
2026-06-11
66 papers in source corpus 40 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Histone H1.2 is a linker histone that functions both as a structural organizer of chromatin and as a context-dependent regulator of transcription, the DNA-damage response, and apoptosis (PMID:14505568, PMID:38530350). As a structural protein it universally localizes to the nuclear periphery and is enriched at low-GC, lamina-associated, H3K27me3-marked heterochromatic domains, where its depletion triggers global chromatin decompaction (PMID:24476918, PMID:38530350), and it establishes facultative heterochromatin in differentiating cells (PMID:23645681). Its N-terminal domain sets nucleosome-binding affinity while its C-terminal tail dictates the geometry of the globular-domain interaction and reads EZH2-deposited H3K27me3 to direct gene-specific recruitment and silencing (PMID:22334665, PMID:26581166). H1.2 represses transcription through several routes: it assembles a YB1/PURα-containing complex that binds p53 and blocks p300-mediated chromatin acetylation at the Bax promoter (PMID:18258596), forms a chromatin-bound complex with pRb to repress E2F target genes and enforce cell-cycle arrest (PMID:28614707), and is deposited by BRG1 to silence progestin-repressed genes (PMID:27390128); conversely, it can act as a transactivator by binding Ser2-phosphorylated RNAPII and bridging the Cul4A E3 ligase and PAF1 elongation complex to drive H4K31 ubiquitylation and productive elongation (PMID:24360965). In response to DNA double-strand breaks, H1.2 is released from chromatin in a p53-dependent manner—facilitated by PARP1-mediated PARylation of its C-terminus and proteasomal turnover—and translocates to mitochondria where its C-terminal K/RVVKP motif directly activates BAK to release cytochrome c, and it further nucleates an APAF-1/CASP-9 apoptosome to drive apoptosis (PMID:14505568, PMID:29844578, PMID:32786407, PMID:17618626). This activity is tuned by post-translational control: DNA-PK phosphorylates H1.2 at T146 to weaken p53 binding and dampen its repressive and pro-apoptotic functions (PMID:22249259), while ITCH-mediated polyubiquitination of H1.2 suppresses RNF8/RNF168-dependent 53BP1 foci (PMID:30517763). H1.2 also stabilizes the transcription factors NRF2 and HIF-1α to support antioxidant and hypoxic adaptive programs (PMID:37729198, PMID:39178313), and contributes to innate antiviral responses by potentiating MDA5/IRF3 signaling while negatively regulating cGAS via TRIM28-mediated degradation (PMID:38399950, PMID:41972757).

Mechanistic history

Synthesis pass · year-by-year structured walk · 34 steps
  1. 2003 High

    Established that a linker histone is not merely structural but can transmit a nuclear DNA-damage signal to mitochondria, defining H1.2 as a specific apoptotic effector distinct from other H1 variants.

    Evidence Subcellular fractionation, isolated-mitochondria cytochrome c release, and H1.2-deficient mice after X-ray irradiation

    PMID:14505568

    Open questions at the time
    • Molecular mechanism of Bak engagement not resolved at this stage
    • How p53 directs H1.2 nuclear release left undefined
  2. 2003 Medium

    Identified H1.2 as a substrate of denitrase activity, a biochemical observation about its single tyrosine that remains peripheral to its chromatin functions.

    Evidence In vitro denitrase activity assay on chemically nitrated recombinant H1.2

    PMID:12719531

    Open questions at the time
    • Physiological relevance of H1.2 nitration/denitration not established
    • Single in vitro study without cellular validation
  3. 2007 Medium

    Extended H1.2's apoptotic role beyond Bak by showing it positively regulates apoptosome assembly downstream of cytochrome c.

    Evidence Affinity labeling, mass spectrometry, and cell-free caspase activation reconstituting an H1.2/APAF-1/CASP-9/cytochrome c complex after UV

    PMID:17618626

    Open questions at the time
    • Single cell-free study without in vivo confirmation
    • Stoichiometry and direct binding interface with APAF-1 unresolved
  4. 2008 High

    Defined H1.2 as a sequence-specific transcriptional repressor of the p53 program by reconstituting an inhibitory complex that blocks p300 acetylation.

    Evidence Affinity purification of an H1.2/YB1/PURα complex, in vitro chromatin transcription, Co-IP, and ChIP/RNAi at the Bax promoter

    PMID:18258596

    Open questions at the time
    • How the same protein switches between repressor and apoptotic effector not addressed
    • Genome-wide scope of YB1/PURα-dependent repression unknown
  5. 2008 Medium

    Provided in-cell evidence that H1.2 physically relocates to mitochondria and partners with Bak after DSBs, linking the 2003 release event to its mitochondrial target.

    Evidence Subcellular fractionation, Bak co-localization, and mitochondrial permeabilization assay after bleomycin

    PMID:17879944

    Open questions at the time
    • Direct binding residues not mapped
    • Single-lab imaging-based localization
  6. 2010 High

    Resolved why H1 subtypes are non-redundant by showing H1.2 has an intrinsically distinct nucleosome-binding orientation governed by separable N- and C-terminal contributions.

    Evidence Domain-swap and point mutagenesis with dual-color FRAP in living cells

    PMID:20444700 PMID:22334665

    Open questions at the time
    • Structural basis of the altered globular-domain geometry not solved
    • Functional consequence for specific target genes not tested here
  7. 2009 Medium

    Mapped cell-cycle-coupled phosphorylation of H1.2, hinting that PTMs target it to replication and transcription sites.

    Evidence Phospho-specific antibodies and immunofluorescence in synchronized HeLa cells

    PMID:19609548

    Open questions at the time
    • Responsible kinase not identified
    • Functional output of Ser172 phosphorylation undefined
  8. 2012 High

    Identified DNA-PK phosphorylation of H1.2 at T146 as a molecular switch that disrupts the p53–H1.2 interaction and de-represses p53-driven apoptosis.

    Evidence In vitro kinase assay, Co-IP, reporter assays, and apoptosis readouts with phospho-/acetylation-mimetic mutants

    PMID:22249259

    Open questions at the time
    • In vivo regulation of T146 phosphorylation not established
    • Crosstalk with the mitochondrial apoptotic function not examined
  9. 2013 High

    Showed H1.2 can act as a transactivator, bridging Cul4A and PAF1 to deposit elongation-promoting histone marks, demonstrating a positive role opposite to its repressive activities.

    Evidence Reciprocal Co-IP, ChIP for H4K31ub/H3K4me3/H3K79me2, and RNAi of H1.2/Cul4A/PAF1

    PMID:24360965

    Open questions at the time
    • What determines repressor-versus-activator mode at a given locus unknown
    • Direct catalytic relationship to Cul4A ubiquitylation not defined
  10. 2013 High

    Demonstrated a developmental structural role: H1.2 builds facultative heterochromatin needed for rod photoreceptor nuclear integrity.

    Evidence Triple-knockout mice with electron microscopy, immunofluorescence, and nucleosomal repeat-length analysis

    PMID:23645681

    Open questions at the time
    • Redundancy with H1e/H1(0) not fully separated
    • H1.2-specific contribution within the triple KO not isolated
  11. 2014 High

    Defined H1.2's distinctive genome-wide distribution, anchoring its repressive function to low-GC, lamina-associated heterochromatic domains.

    Evidence ChIP-seq with variant-specific antibodies and HA-tagged variants in breast cancer cells

    PMID:24476918

    Open questions at the time
    • Mechanism targeting H1.2 to LADs not addressed here
    • Causality between enrichment and repression correlative
  12. 2015 High

    Identified H3K27me3 recognition by the H1.2 C-terminal tail as the recruitment mechanism explaining its heterochromatin targeting and silencing.

    Evidence ChIP, H3K27me3-nucleosome binding assays, and C-terminal mutagenesis with gene-expression readout

    PMID:26581166

    Open questions at the time
    • Structural mode of tail–H3K27me3 contact not solved
    • Whether recruitment is direct or EZH2-coupled at all loci unclear
  13. 2016 High

    Showed targeted H1.2 deposition can be actively directed by a chromatin remodeler (BRG1) downstream of hormone signaling to repress specific promoters.

    Evidence ChIP, Co-IP, and knockdown with nucleosome positioning analysis at progestin-repressed genes

    PMID:27390128

    Open questions at the time
    • Generality beyond progesterone-responsive genes untested
    • How BRG1 selects H1.2 versus other variants unknown
  14. 2017 High

    Established H1.2 as a major pRb partner that augments pRb chromatin loading and E2F target repression, linking it directly to cell-cycle control.

    Evidence Reciprocal Co-IP, genome-wide pRb ChIP-seq, knockdown, and proliferation assays

    PMID:28614707

    Open questions at the time
    • Whether H1.2 acts upstream or downstream of pRb phosphorylation unclear
    • Structural basis of the H1.2–pRb interaction undefined
  15. 2017 High

    Connected H1.2 to autophagy regulation via a SIRT1/HDAC1–H4K16ac–ATG axis in a disease (diabetic retinopathy) context.

    Evidence Overexpression/knockdown in cells, AAV in vivo overexpression, and siRNA in diabetic mice

    PMID:28409999

    Open questions at the time
    • Direct versus indirect control of SIRT1/HDAC1 not separated
    • Relevance outside retinal tissue untested
  16. 2018 High

    Revealed that PARP1-driven PARylation and degradation displaces H1.2 from chromatin to permit ATM activation, recasting H1.2 release as a regulated step in DSB repair signaling.

    Evidence Direct H1.2–ATM HEAT-domain binding, PARylation assay, PARP1 depletion, PARylation-dead mutant, and repair assays

    PMID:29844578

    Open questions at the time
    • Relationship between this displacement and the pro-apoptotic mitochondrial pool not reconciled
    • PARylation site(s) not precisely mapped
  17. 2018 Medium

    Added an interaction-based repression mechanism via the mH2A1.2/HP1α/H1.2 module controlling immune-relevant gene silencing.

    Evidence Co-IP, ChIP, knockdown, and osteoclastogenesis assays in prostate cancer cells

    PMID:29925860

    Open questions at the time
    • Single-lab, single-context observation
    • Direct versus bridged H1.2–mH2A1.2 contact not resolved
  18. 2018 Medium

    Placed H1.2 at nucleolar organizer regions with UBF, implicating it in mitotic rDNA chromatin organization.

    Evidence UBF-Sepharose pulldown and imaging during mitosis and after rRNA synthesis inhibition

    PMID:29301938

    Open questions at the time
    • Functional role at NORs not tested
    • Whether interaction is direct unknown
  19. 2019 High

    Defined ITCH-mediated polyubiquitination of H1.2 as an AKT-controlled brake on 53BP1-dependent DDR signaling.

    Evidence Co-IP, ubiquitination assay, 53BP1 foci imaging, and AKT inhibition

    PMID:30517763

    Open questions at the time
    • Ubiquitination sites on H1.2 not mapped
    • Integration with PARP1-driven displacement not addressed
  20. 2020 High

    Pinpointed the K/RVVKP motif as the minimal C-terminal determinant for direct BAK activation and cytochrome c release, providing the structural mechanism for H1.2's apoptotic effector function.

    Evidence In vitro cytochrome c release, K/RVVKP mutagenesis, direct BAK binding, and peptide competition

    PMID:32786407

    Open questions at the time
    • In vivo requirement of the motif not tested
    • Conformational change induced in BAK not defined
  21. 2020 High

    Revealed a lineage-specific role for H1.2 in granulopoiesis, where its loss redirects differentiation toward an eosinophil program.

    Evidence Genome-wide CRISPR screen, subtype KO, transcriptomics, and differentiation assays in human and mouse cells

    PMID:32391789

    Open questions at the time
    • Target genes mediating lineage choice not pinpointed
    • Overlap of H1.2 and H1.4 functions not separated
  22. 2020 Medium

    Linked oncogenic K-Ras-ERK signaling to loss of H1.2 T146 phosphorylation via MDM2-mediated DNA-PK degradation, connecting H1.2 PTM control to tumor growth.

    Evidence K-Ras transfection, ChIP, phospho-mimetic mutant, and proliferation/migration assays in bladder cancer cells

    PMID:31032946

    Open questions at the time
    • Single-study mechanistic chain
    • Direct DNA-PK–MDM2 link not biochemically isolated
  23. 2022 Medium

    Identified an H1.2–STAT3 feed-forward loop driving hepatocellular carcinoma proliferation.

    Evidence Overexpression/knockdown, STAT3 ChIP at the H1.2 promoter, in vivo models, and STAT3 inhibition

    PMID:35294987

    Open questions at the time
    • Mechanism by which H1.2 promotes STAT3 activation undefined
    • Single-cancer-type context
  24. 2023 High

    Established H1.2 as a stabilizer of NRF2 that sustains glutathione synthesis, defining a feed-forward antioxidant cycle promoting NSCLC progression and chemoresistance.

    Evidence Co-IP, NRF2 ChIP at GCLC, H1c-KO/Kras mouse model, and ROS/GSH/cisplatin assays

    PMID:37729198

    Open questions at the time
    • Whether H1.2 acts on NRF2 in the nucleus or cytoplasm not fully resolved
    • Direct binding interface not mapped
  25. 2023 High

    Demonstrated a metabolic role: H1.2 represses thermogenesis by activating Il10rα transcription in beige adipocytes.

    Evidence Adipocyte-specific KO mice, ChIP at Il10rα, and Il10rα rescue with cold-tolerance phenotyping

    PMID:37414781

    Open questions at the time
    • How H1.2 activates rather than represses this promoter not mechanistically explained
    • Upstream signals regulating adipocyte H1.2 unknown
  26. 2023 Medium

    Added p16 repression by promoter-bound H1.2, with YB-1 sustaining H1.2 levels and recruitment.

    Evidence siRNA knockdown, ChIP, and qRT-PCR

    PMID:37500167

    Open questions at the time
    • Single-lab ChIP-based study
    • Senescence consequences not functionally tested
  27. 2024 High

    Showed PTM-state of chromatin-bound H1.2 reshapes its proteome-wide interactome, including recruitment of DSB-repair factors.

    Evidence Chemically defined modified chromatosomes, affinity-MS interactomes, and in vitro ligation assay

    PMID:37994785

    Open questions at the time
    • In-cell relevance of identified interactors not validated
    • Functional repair contribution beyond ligation assay untested
  28. 2024 High

    Linked H1.2 to ALS pathology: PARylation-dependent FUS–H1.2 binding promotes mutant FUS aggregation and motor-neuron toxicity.

    Evidence iPSC-motor-neuron interactome, PARP1 inhibition, H1.2 perturbation, and C. elegans models

    PMID:39167487

    Open questions at the time
    • Whether H1.2 acts in cytoplasm or via chromatin in this context unclear
    • Direct FUS–H1.2 contact versus PARP1-bridged not separated
  29. 2024 Medium

    Extended H1.2's transcription-factor stabilizing role to HIF-1α, supporting hypoxic adaptation.

    Evidence Co-IP with HIF-1α PAS domains, dimerization assay, PARP1 inhibition, and a knock-in mouse hypoxia challenge

    PMID:39178313

    Open questions at the time
    • Direct binding interface not structurally defined
    • Single-lab mechanistic chain
  30. 2024 Medium

    Defined a positive antiviral role through H1.2 potentiation of MDA5/IRF3 signaling against RNA virus infection.

    Evidence Overexpression/knockdown, Co-IP with MDA5 and IRF3, and IFN-β/viral assays

    PMID:38399950

    Open questions at the time
    • Direct versus indirect MDA5/IRF3 engagement unclear
    • Single-study, single-virus context
  31. 2024 High

    Confirmed H1.2's universal peripheral localization and its causal requirement for global chromatin compaction across cell types.

    Evidence Super-resolution microscopy and siRNA knockdown with quantitative decompaction readout

    PMID:38530350

    Open questions at the time
    • What targets H1.2 to the periphery not addressed
    • Relationship between compaction and gene-specific repression not bridged
  32. 2025 Medium

    Identified Galectin-1 as a modulator that enhances H1.2 PARylation/degradation to favor ATM/NBS1 repair signaling over apoptosis in lung cancer.

    Evidence Proximity-labeling proteomics, Co-IP, PARylation assay, ATM/NBS1 phosphorylation, and in vivo tumor model

    PMID:40365664

    Open questions at the time
    • Direct Gal-1–H1.2 binding versus PARP1-mediated bridging unclear
    • Single-lab study
  33. 2026 Medium

    Defined H1.2 as a negative regulator of cGAS, both inactivating it on chromatin and recruiting TRIM28 for its nuclear degradation, with viral suppression of H1.2 unleashing IFN-I.

    Evidence Co-IP with cGAS/TRIM28, cGAS Lys240 activity assay, HSV-1 infection model, and Sp1 inhibition in vivo

    PMID:41972757

    Open questions at the time
    • Direct H1.2–cGAS contact versus chromatin-mediated effect not fully separated
    • Single-study mechanism
  34. 2026 Medium

    Identified USP7 as a deubiquitinase that stabilizes H1.2 to support DNA repair, adding a counterweight to ubiquitin-driven H1.2 turnover.

    Evidence Proteomics, ubiquitin-omics, Co-IP, comet/γ-H2AX assays, USP7 inhibition, and xenografts

    PMID:41639524

    Open questions at the time
    • DUB site specificity on H1.2 not mapped
    • Single-tumor-type context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How H1.2 toggles between mutually opposed roles—structural glue, gene-specific repressor, transactivator, transcription-factor stabilizer, and cytoplasmic apoptotic effector—through its post-translational modification code and localization remains unresolved.
  • No unified model integrating chromatin and mitochondrial pools
  • Structural basis of most direct protein interactions undefined
  • In vivo hierarchy of competing PTMs (T146 phosphorylation, PARylation, ubiquitination, SUMOylation) not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3 GO:0005198 structural molecule activity 3 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005739 mitochondrion 3 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-1640170 Cell Cycle 1
Partners
ATMBAK1ITCHNFE2L2PARP1RB1TP53USP7
Complex memberships
APAF-1/CASP-9 apoptosomeCul4A-PAF1 elongation complexH1.2-YB1-PURα repressor complexpRb-H1.2 chromatin complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Histone H1.2 is released from the nucleus to the cytoplasm in a p53-dependent manner following X-ray irradiation (DNA double-strand breaks), and uniquely among H1 variants, H1.2 (but not other H1 forms) induces cytochrome c release from isolated mitochondria in a Bak-dependent manner, transmitting apoptotic signals from the nucleus to mitochondria. Subcellular fractionation, isolated mitochondria cytochrome c release assay, H1.2-deficient mice, genetic knockdown/knockout with apoptosis phenotype readouts Cell High 14505568
2003 Histone H1.2 is identified as a substrate for denitrase activity; denitrase specifically removes nitrotyrosine from the single tyrosine residue of H1.2 in an enzymatic, time-dependent, heat- and trypsin-sensitive reaction requiring no additional cofactors. 2D-gel electrophoresis, on-blot enzyme assay, recombinant purified H1.2 chemical nitration, in vitro denitrase activity assay Proceedings of the National Academy of Sciences of the United States of America Medium 12719531
2007 Upon UV irradiation, histone H1.2 forms a protein complex with APAF-1, CASP-9, and cytochrome c, and in cell-free systems H1.2 triggers activation of CASP-3 and CASP-7 via APAF-1 and CASP-9, acting as a positive regulator of apoptosome formation. Affinity labeling, mass spectrometry, cell-free caspase activation assay FEBS letters Medium 17618626
2008 After bleomycin-induced DNA double-strand breaks, histone H1.2 is translocated from the nucleus to mitochondria and co-localizes with Bak in mitochondria, supporting a role in transmitting apoptotic signals. Western blotting (subcellular fractionation), immunofluorescence co-localization with Bak, MitoCapture mitochondrial permeabilization assay Journal of cellular biochemistry Medium 17879944
2008 H1.2 forms a stable complex with cofactors including YB1 and PURα, and ribosomal proteins, that represses p53-dependent, p300-mediated chromatin transcription; H1.2 directly interacts with p53, blocking p300-mediated chromatin acetylation. ChIP and RNAi confirmed recruitment of YB1, PURα, and H1.2 to the Bax promoter is required for repression of p53-induced transcription. Affinity purification of H1.2 complex, in vitro chromatin transcription assay, Co-IP, ChIP, RNA interference The Journal of biological chemistry High 18258596
2009 Phosphorylation of H1.2 at Ser172 co-localizes to DNA replication and transcription sites in HeLa cells, suggesting site-specific phosphorylation of H1.2 is associated with distinct nuclear processes during the cell cycle. Phospho-specific antibodies, immunofluorescence co-localization in synchronized HeLa cells, kinase inhibitor staurosporine treatment Chromosoma Medium 19609548
2010 The nucleosome interaction surface of linker histone H1c (H1.2) is distinct from that of H1(0); the N-terminal domain governs overall binding affinity, while the C-terminal domain alters the chromatin interaction surface of the globular domain, indicating subtypes bind chromatin with intrinsically different orientations. Site-directed mutagenesis, domain-swap constructs, dual-color FRAP in living cells The Journal of biological chemistry High 20444700
2012 DNA-PK phosphorylates H1.2 at T146, which impairs H1.2 binding to p53 and attenuates H1.2-mediated suppression of p53 transactivation; simultaneously, p300-mediated acetylation of p53's C-terminal domain disrupts the p53–H1.2 interaction. Point mutations mimicking these modification states increase p53-induced apoptosis. In vitro kinase assay, Co-IP, reporter gene assay, apoptosis assay with phospho-mimetic/acetylation-mimetic mutants Oncogene High 22249259
2012 The N-terminal and C-terminal domains of linker histone H1c (H1.2) contribute differentially to nucleosome binding: the N-terminal domain determines overall binding affinity, and the C-terminal domain alters the geometry of the globular domain-nucleosome interaction. Domain-swap and point mutagenesis, dual-color FRAP assay in living cells The Journal of biological chemistry High 22334665
2013 H1.2 stably interacts with Cul4A E3 ubiquitin ligase and PAF1 elongation complexes; this interaction drives H4K31 ubiquitylation, H3K4me3, and H3K79me2 at target genes to potentiate transcription. H1.2 binds the Ser2-phosphorylated form of RNAPII and bridges the Cul4A–PAF1 interaction. Individual knockdown of H1.2, Cul4A, or PAF1 abolishes the corresponding histone marks and reduces target gene transcription. Co-IP, ChIP, RNA interference knockdown, histone modification analysis Cell reports High 24360965
2013 During mouse rod photoreceptor maturation, H1c (H1.2) levels increase dramatically and contribute to facultative heterochromatin condensation and structural integrity of rod nuclei; triple knockout (H1c/H1e/H1(0)) causes larger nuclei, decreased heterochromatin area, and altered exposure of H3K9me2 marks, indicating H1c establishes facultative heterochromatin territory. Genetic knockout (triple KO mice), electron microscopy, immunofluorescence, chromatin analysis, nucleosomal repeat length measurement The Journal of biological chemistry High 23645681
2014 H1.2 is less abundant than other H1 variants at transcription start sites of inactive genes; promoters enriched in H1.2 tend to be repressed; H1.2 is enriched at low-GC chromosomal domains and lamina-associated domains, showing the most distinct genomic distribution pattern among H1 variants. ChIP-seq with variant-specific antibodies and HA-tagged H1 variants in breast cancer cells Nucleic acids research High 24476918
2014 H1.2 localizes to the cytoplasm via a mechanism sensitive to the nuclear export inhibitor leptomycin B (LMB) during cytokine withdrawal-induced apoptosis in T-effector cells; H1.2 is found in a complex with proapoptotic mitochondrial Bak, and its cytoplasmic localization is regulated by JNK signaling. LMB inhibitor treatment, subcellular fractionation, Co-immunoprecipitation with Bak, apoptosis assay International journal of cell biology Medium 24688545
2015 H1.2 is recruited to distinct chromatin regions dependent on EZH2-mediated H3K27me3; the C-terminal tail of H1.2 is required for binding H3K27me3 nucleosomes, and mutations of three H1.2-specific amino acids in the C-terminal domain abrogate binding to H3K27me3 nucleosomes and fail to silence target genes, establishing H3K27me3 as a key mechanism governing H1.2 recruitment. ChIP, nucleosome binding assay with H3K27me3 nucleosomes, C-terminal tail mutagenesis, gene expression analysis Scientific reports High 26581166
2016 Hormone-activated progesterone receptor recruits BRG1, which interacts with H1.2 to facilitate its deposition and stabilize nucleosome positioning around the TSS at progestin-repressed genes; BRG1 but not the full BAF complex is recruited to these repressed promoters, and H1.2 deposition is required for gene repression. ChIP, Co-IP, knockdown experiments, genomic positioning analysis in breast cancer cells The EMBO journal High 27390128
2017 H1.2 overexpression in retinal cells upregulates SIRT1 and HDAC1 to maintain deacetylation of H4K16, leading to upregulation of ATG proteins and promotion of autophagy. AAV-mediated H1.2 overexpression in retinas increases autophagy, inflammation, and neuron loss; siRNA knockdown attenuates diabetes-induced autophagy and retinal pathology. Overexpression and knockdown in cell lines, AAV-mediated in vivo overexpression, siRNA knockdown in diabetic mice, Western blotting, immunofluorescence Autophagy High 28409999
2017 H1.2 is a major interaction partner of the retinoblastoma tumor suppressor pRb; H1.2 and pRb form a chromatin-bound complex on E2F target genes, H1.2 augments global pRb association with chromatin, enhances pRb-mediated transcriptional repression of E2F target genes, and facilitates pRb-dependent cell-cycle arrest. Co-IP, ChIP-seq for genome-wide pRb distribution, knockdown, cell proliferation assays Cell reports High 28614707
2018 H1.2 directly interacts with the ATM HEAT repeat domain and inhibits MRN complex-dependent ATM recruitment, preventing aberrant ATM activation. Upon DNA damage, PARP1-mediated poly-ADP-ribosylation (PARylation) of the H1.2 C-terminus causes its rapid chromatin dissociation followed by proteasomal degradation; blocking H1.2 displacement via PARP1 depletion or PARylation-dead mutation impairs ATM activation and DNA damage repair. Co-IP, in vitro binding assay (H1.2–ATM HEAT domain), PARylation assay, PARP1 depletion, H1.2 PARylation-dead mutant, DNA damage repair assays Cell research High 29844578
2018 H1.2 is a novel component of nucleolar organizer regions (NORs); during mitosis H1.2 and UBF are co-recruited to NORs, identified by UBF-Sepharose pulldown. Inhibiting rRNA synthesis in interphase induces NOR-like structures containing both UBF and H1.2; NORs isolated from fragmented chromosomes remain intact and contain both proteins. UBF-Sepharose affinity pulldown, immunofluorescence co-localization during mitosis, inhibition of rRNA synthesis The Journal of biological chemistry Medium 29301938
2018 mH2A1.2 directly interacts with HP1α and H1.2 to maintain the inactive state of the lymphotoxin beta (LTβ) gene in prostate cancer cells; H1.2 has intrinsic ability to inhibit osteoclast differentiation in a mH2A1.2-dependent manner. Co-IP, ChIP, knockdown functional assays, osteoclastogenesis assay Oncogene Medium 29925860
2019 AKT phosphorylates ITCH at Ser257, leading to its nuclear translocation and ITCH-mediated polyubiquitination of H1.2; this polyubiquitination suppresses RNF8/RNF168-dependent 53BP1 foci formation, impairing the DNA damage response. Impaired ITCH nuclear translocation or H1.2 polyubiquitination sensitizes cells to replication stress. Co-IP, ubiquitination assay, 53BP1 foci immunofluorescence, AKT inhibitor, knockdown/overexpression Nucleic acids research High 30517763
2020 Loss of H1.2 (and H1.4) in PLB-985 cells induces an eosinophil-like transcriptional program, negatively regulating neutrophil lineage differentiation; this effect was confirmed in murine bone marrow stem cells, demonstrating a subtype-specific role for H1.2 in granulopoiesis. Genome-wide CRISPR/Cas9 screen, systematic H1 subtype KO, transcriptomic analysis, differentiation assays in human and mouse cells eLife High 32391789
2020 The C-terminal domain (CTD) of H1.2, specifically the K/RVVKP motif, directly interacts with BAK and stimulates mitochondrial cytochrome c release in vitro in a mitochondrial permeability transition-independent manner; substitution of a single valine with threonine in the K/RVVKP motif abolishes cytochrome c release. In vitro mitochondrial cytochrome c release assay, mutagenesis of K/RVVKP motif, direct binding assay with recombinant BAK, synthetic peptide competition Biochemistry High 32786407
2020 K-Ras-ERK1/2 signaling inhibits H1.2 phosphorylation at T146 through MDM2-mediated proteasomal degradation of DNA-PK; H1.2 T146 phosphorylation regulates transcription of downstream genes (NT5E, GDF15, CARD16, CYR61, IGFBP3, WNT16B) and its loss promotes bladder cancer cell growth and migration. K-Ras mutant transfection, Western blot, ChIP, MTT/colony/transwell assays, qRT-PCR, phospho-mimetic mutation (T146E) Journal of cellular physiology Medium 31032946
2020 MTA1 promotes proteasomal degradation of DNA-PK (via MDM2 E3 ligase), thereby reducing DNA-PK-mediated phosphorylation of H1.2 at T146; ectopic expression of H1.2 T146ph rescues MTA1-induced HCC cell growth and migration. NOTE: The corresponding paper (PMID 32435614) was subsequently retracted (PMID 42211522). Western blot, ChIP, proteasome inhibitor rescue, MDM2 knockout, H1.2 T146ph overexpression — RETRACTED Frontiers in oncology Low 32435614 42211522
2022 H1.2 regulates STAT3 activation in HCC; mechanistically, H1.2 and STAT3 form a feed-forward loop in which H1.2 promotes STAT3 activation and STAT3 transcriptionally upregulates H1.2 by binding its promoter; disrupting this loop by STAT3 knockdown or inhibitors rescues H1.2 overexpression-induced proliferation. Overexpression/knockdown in HCC cell lines, ChIP for STAT3 at H1.2 promoter, in vivo KO/KD mouse models, STAT3 inhibitor treatment Cancer science Medium 35294987
2023 H1.2 interacts with NRF2 and enhances its nuclear level and stability, promoting NRF2 binding to the GCLC promoter and consequent transcription, thereby sustaining glutathione synthesis; NRF2 also transcriptionally upregulates H1.2, forming a feed-forward antioxidant cycle that promotes NSCLC progression and chemoresistance. Co-IP (H1.2–NRF2 interaction), ChIP (NRF2 at GCLC promoter), H1c KO mouse crossed with Kras NSCLC model, ROS/GSH measurement, cisplatin sensitivity assay Proceedings of the National Academy of Sciences of the United States of America High 37729198
2023 H1.2 binds to the promoter of Il10rα (encoding an IL-10 receptor subunit) and positively regulates its expression to suppress thermogenesis in beige adipocytes; adipocyte-specific H1.2 knockout promotes iWAT browning and cold tolerance, while Il10rα overexpression negates these effects. Adipocyte-specific H1.2 KO mice (H1.2AKO), ChIP (H1.2 at Il10rα promoter), overexpression of Il10rα in iWAT, cold tolerance and metabolic phenotyping Nature communications High 37414781
2023 H1.2 directly binds to the p16 promoter to repress its transcription; YB-1, a component of the H1.2 complex, positively regulates H1.2 expression levels, and its silencing decreases H1.2 binding at the p16 promoter. siRNA knockdown, ChIP assay, qRT-PCR, immunoblotting Anticancer research Medium 37500167
2024 ALS-associated mutant FUS (FUSP525L) shows increased interaction with PARP1, promoting PARylation and binding of FUS to histone H1.2; inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, stress granule alterations, and apoptosis in iPSC-derived motor neurons; elevated H1.2 worsens FUS-ALS phenotypes driven by its intrinsically disordered terminal domains; knockdown of H1.2 and PARP1 orthologs in C. elegans also decreases FUSP525L aggregation. Interactome of FUSP525L in iPSC-derived motor neurons, PARP1 inhibition, H1.2 knockdown/overexpression, C. elegans models, aggregation and apoptosis assays Cell reports High 39167487
2024 Site-specifically ubiquitylated and acetylated H1.2 in intact chromatosomes show distinct proteome-wide interactomes; chromatin-bound H1.2 recruits proteins involved in DNA double-strand break repair, validated by in vitro ligation assay, and post-translational modifications of H1.2 alter these interactions on a proteome-wide scale. Chemical biology assembly of site-specifically modified chromatosomes, affinity enrichment mass spectrometry, in vitro ligation assay for DSB repair Nucleic acids research High 37994785
2024 H1.2 overexpression inhibits EMCV replication by enhancing MDA5-mediated IFN-β signaling; H1.2 interacts with MDA5 and IRF3 during EMCV infection, upregulates MDA5 pathway proteins, and facilitates EMCV-induced phosphorylation and nuclear translocation of IRF3. Overexpression/knockdown in HEK293T, Co-IP (H1.2 with MDA5 and IRF3), viral plaque/RT-PCR assays, IFN-β reporter assay, IRF3 phosphorylation and localization Viruses Medium 38399950
2024 H1.2 directly interacts with HIF-1α PAS domains and promotes HIF-1α stability and its dimerization with HIF-1β, enhancing HIF-1α transcriptional activity; H1.2 expression is negatively regulated by PARP1 (its inhibitor), and higher H1.2 in naked mole rat cells contributes to anoxic adaptation. Co-IP (H1.2–HIF-1α), H1.2 overexpression in fibroblasts, HIF-1α dimerization assay, PARP1 inhibition, H1.2 knock-in mouse model with hypoxia challenge PLoS biology Medium 39178313
2024 H1.2 universally localizes to the nuclear periphery and co-localizes with compacted DNA in all human cell lines examined; H1.2 knockdown, alone or combined, triggers global chromatin decompaction, demonstrating a variant-specific role in maintaining peripheral chromatin compaction. Super-resolution microscopy, immunofluorescence imaging of H1 variants, H1.2 siRNA knockdown with chromatin compaction readout eLife High 38530350
2006 C-terminal fragments of histone H1.2 are endogenous furin inhibitors purified from porcine liver; the inhibitory activity resides in the C-terminal lysine-rich domain, with Ki values ~2×10⁻⁷ M; full-length H1.2 inhibits furin with lower activity; a 36 amino acid peptide containing the reactive site retains inhibitory activity. Purification by chromatography from porcine liver, furin inhibition assay (Ki determination), gene cloning and sequencing, synthetic peptide assay The FEBS journal Medium 16956366
2015 PARP-1 binds the EPHX1 proximal promoter and histone H1.2 (complexed with Aly) binds a regulatory intron 1 site to regulate EPHX1 transcription; mutations at the H1.2-binding site in the Amish population reduce EPHX1 expression and are associated with hypercholanemia. Biotinylated oligonucleotide pulldown with mass spectrometry, reporter gene assay PloS one Medium 25992604
2026 H1.2 inhibits cGAS by affecting the activity of cGAS Lys240, promoting cGAS binding to chromatin (inactivating it), and by recruiting TRIM28 to degrade cGAS in the nucleus; HSV-1 infection downregulates H1.2 by reducing Sp1 mRNA levels, allowing cGAS release and IFN-I activation. Overexpression/knockdown of H1.2 in HSV-1 infection model, Co-IP (H1.2 with cGAS/TRIM28), cGAS Lys240 activity assay, Sp1 inhibitor (plicamycin) in vivo, IFN-β reporter assay mBio Medium 41972757
2025 Galectin-1 (Gal-1) interacts with both PARP1 and H1.2 in lung cancer cells; upon etoposide-induced DSBs, Gal-1 enhances H1.2 interaction with PARP1 and accelerates H1.2 PARylation and degradation, which activates downstream ATM and NBS1 DNA repair signaling and reduces apoptosis. Proximity-labeling proteomics, Co-IP, etoposide treatment, H1.2 PARylation assay, ATM/NBS1 phosphorylation, Gal-1 overexpression/knockdown, in vivo tumor model The FEBS journal Medium 40365664
2025 SETDB1 binds to SUMOylated histone H1.2 (and H1.4), and SUMOylated H1.2 co-localizes with H3K9me3 at repetitive regions of the genome. PLAMseq (TurboID proximity-labeling + ChIP-seq), mass spectrometry, western blot validation bioRxiv (preprint)preprint Low
2025 The majority of H1.2 behaves like a liquid ('glue') inside chromatin domains, mediating dynamic multivalent electrostatic interactions between nucleosomes rather than binding stably; rapid depletion of H1.2 leads to decondensed chromatin domains both in cells and in molecular dynamics simulations. Single-molecule live-cell imaging (PALM/SPT), multiscale molecular dynamics simulations, rapid H1.2 depletion with chromatin domain decompaction assay bioRxiv (preprint)preprint Medium
2025 m6A modification of H1-2 mRNA promotes its stability through IGF2BP1 binding and enhances its translation through the combined action of IGF2BP1 and hnRNPD, providing a post-transcriptional regulatory mechanism for H1.2 expression. MeRIP-seq, m6A inhibition, siRNA-mediated depletion of m6A readers (YTHDF2, IGF2BP1, hnRNPD), mRNA stability and translation assays bioRxiv (preprint)preprint Low
2026 USP7 deubiquitinase interacts with histone H1.2 and protects it from proteasome-mediated degradation; USP7-H1.2 interaction facilitates DNA repair in pancreatic neuroendocrine neoplasm cells. Proteomics, ubiquitin-omics, Co-IP, comet assay, γ-H2AX immunofluorescence, USP7 inhibitor (P005091), xenograft model Science China. Life sciences Medium 41639524

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Involvement of histone H1.2 in apoptosis induced by DNA double-strand breaks. Cell 274 14505568
2006 The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiology of disease 206 17174556
2005 The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Human molecular genetics 181 16000317
2003 Histone H1.2 is a substrate for denitrase, an activity that reduces nitrotyrosine immunoreactivity in proteins. Proceedings of the National Academy of Sciences of the United States of America 104 12719531
2008 Isolation and characterization of a novel H1.2 complex that acts as a repressor of p53-mediated transcription. The Journal of biological chemistry 97 18258596
2017 Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy. Autophagy 90 28409999
2014 Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2. Nucleic acids research 84 24476918
2009 Rapid multiplex reverse transcription-PCR typing of influenza A and B virus, and subtyping of influenza A virus into H1, 2, 3, 5, 7, 9, N1 (human), N1 (animal), N2, and N7, including typing of novel swine origin influenza A (H1N1) virus, during the 2009 outbreak in Milwaukee, Wisconsin. Journal of clinical microbiology 74 19641063
2018 Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair. Cell research 72 29844578
2013 Linker Histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation. Cell reports 54 24360965
1989 Human spleen histone H1. Isolation and amino acid sequences of three minor variants, H1a, H1c, and H1d. Journal of biochemistry 51 2613692
2013 Developmentally regulated linker histone H1c promotes heterochromatin condensation and mediates structural integrity of rod photoreceptors in mouse retina. The Journal of biological chemistry 49 23645681
2015 Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. Scientific reports 45 26581166
2012 N- and C-terminal domains determine differential nucleosomal binding geometry and affinity of linker histone isotypes H1(0) and H1c. The Journal of biological chemistry 44 22334665
2009 Site-specifically phosphorylated forms of H1.5 and H1.2 localized at distinct regions of the nucleus are related to different processes during the cell cycle. Chromosoma 41 19609548
2012 Functional interplay between p53 acetylation and H1.2 phosphorylation in p53-regulated transcription. Oncogene 40 22249259
2005 Activity of histone H1.2 in infected burn wounds. The Journal of antimicrobial chemotherapy 40 15772144
2008 Histone H1.2 is translocated to mitochondria and associates with Bak in bleomycin-induced apoptotic cells. Journal of cellular biochemistry 35 17879944
2005 Characterization of sequence variations in human histone H1.2 and H1.4 subtypes. The FEBS journal 31 16008566
2016 Hormone-induced repression of genes requires BRG1-mediated H1.2 deposition at target promoters. The EMBO journal 30 27390128
2010 Nucleosome interaction surface of linker histone H1c is distinct from that of H1(0). The Journal of biological chemistry 30 20444700
2018 MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2. Oncogene 27 29925860
2007 Proapoptotic histone H1.2 induces CASP-3 and -7 activation by forming a protein complex with CYT c, APAF-1 and CASP-9. FEBS letters 27 17618626
1982 The structural role of histone H1: properties of reconstituted chromatin with various H1 subfractions (H1-1, H1-2, and H1o). The EMBO journal 22 7188252
2022 Molecular and Cellular Functions of the Linker Histone H1.2. Frontiers in cell and developmental biology 20 35087830
2022 Histone H1.2 promotes hepatocarcinogenesis by regulating signal transducer and activator of transcription 3 signaling. Cancer science 20 35294987
2019 ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response. Nucleic acids research 20 30517763
2008 The effect of age and the H1c MAPT haplotype on MAPT expression in human brain. Neurobiology of aging 20 18276036
2015 Transcription of the Human Microsomal Epoxide Hydrolase Gene (EPHX1) Is Regulated by PARP-1 and Histone H1.2. Association with Sodium-Dependent Bile Acid Transport. PloS one 19 25992604
2011 The linker histone H1C contributes to the SCA7 nuclear phenotype. Nucleus (Austin, Tex.) 18 21970987
2008 Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment. Haematologica 18 18166788
2023 An antioxidant feedforward cycle coordinated by linker histone variant H1.2 and NRF2 that drives nonsmall cell lung cancer progression. Proceedings of the National Academy of Sciences of the United States of America 16 37729198
2017 RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway. Oncotarget 15 29050254
2020 Linker histone H1.2 and H1.4 affect the neutrophil lineage determination. eLife 14 32391789
2010 A histoplasma capsulatum-specific IgG1 isotype monoclonal antibody, H1C, to a 70-kilodalton cell surface protein is not protective in murine histoplasmosis. Clinical and vaccine immunology : CVI 14 20484567
2024 ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes. Cell reports 13 39167487
2017 Linker Histone H1.2 Directs Genome-wide Chromatin Association of the Retinoblastoma Tumor Suppressor Protein and Facilitates Its Function. Cell reports 12 28614707
2003 Histone H1t is not replaced by H1.1 or H1.2 in pachytene spermatocytes or spermatids of H1t-deficient mice. Cytogenetic and genome research 12 15051953
1994 Role of a distal promoter element in the S-phase control of the human H1.2 histone gene transcription. European journal of biochemistry 12 8055927
2023 Linker histone variant H1.2 is a brake on white adipose tissue browning. Nature communications 11 37414781
2020 TADs enriched in histone H1.2 strongly overlap with the B compartment, inaccessible chromatin, and AT-rich Giemsa bands. The FEBS journal 11 32896099
2018 The linker histone H1.2 is a novel component of the nucleolar organizer regions. The Journal of biological chemistry 10 29301938
2020 MTA1 Promotes Hepatocellular Carcinoma Progression by Downregulation of DNA-PK-Mediated H1.2T146 Phosphorylation. Frontiers in oncology 9 32435614
2014 The linker histone h1.2 is an intermediate in the apoptotic response to cytokine deprivation in T-effectors. International journal of cell biology 9 24688545
2023 The role of histone H1.2 in pancreatic cancer metastasis and chemoresistance. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 8 38290407
2006 The potent inhibitory activity of histone H1.2 C-terminal fragments on furin. The FEBS journal 6 16956366
2004 Histone, H1.2: another housekeeping protein that kills. Cancer biology & therapy 6 14726680
2024 Interactome of intact chromatosome variants with site-specifically ubiquitylated and acetylated linker histone H1.2. Nucleic acids research 5 37994785
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
2020 Linker Histone H1.2 Directly Activates BAK through the K/RVVKP Motif on the C-Terminal Domain. Biochemistry 5 32786407
2019 Carcinogenic role of K-Ras-ERK1/2 signaling in bladder cancer via inhibition of H1.2 phosphorylation at T146. Journal of cellular physiology 5 31032946
2000 The recombinant human histones H1 zero and H1.2 cause different toxicity profiles on the human leukemia cell line K562. Anticancer research 5 10953318
1991 Histone H1c decreases markedly in postreplicative stages of chicken spermatogenesis. The International journal of developmental biology 5 1867999
2024 Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-β Signaling Pathway. Viruses 4 38399950
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
2025 Gal-1 promotes lung cancer cell survival by enhancing PARP1/H1.2 interaction to promote DNA repair upon DNA damage response. The FEBS journal 3 40365664
2024 Comparative time-series multi-omics analyses suggest H1.2 involvement in anoxic adaptation and cancer resistance. PLoS biology 3 39178313
2023 HMGN2 and Histone H1.2: potential targets of a novel probiotic mixture for seasonal allergic rhinitis. Frontiers in microbiology 3 37869664
2023 Histone H1.2 Represses the Transcription of the p16 Tumor Suppressor Gene. Anticancer research 2 37500167
2018 Brown Hare's (Lepus europaeus) Histone H1 Variant H1.2 as an Indicator of Anthropogenic Stress. Archives of environmental contamination and toxicology 1 29869686
2026 USP7 protects histone H1.2 from proteasome-mediated degradation to facilitate DNA repair and pancreatic neuroendocrine neoplasms progression. Science China. Life sciences 0 41639524
2026 Linker histone H1.2 inhibits HSV-1-induced IFN response via cGAS. mBio 0 41972757
2026 H1.3 depletion in AML cells prompts H1.2 redistribution, chromatin remodeling and cell cycle defects. Epigenetics & chromatin 0 42098859
2026 Retraction: MTA1 promotes hepatocellular carcinoma progression by downregulation of DNA-PK-mediated H1.2T146 phosphorylation. Frontiers in oncology 0 42211522
2025 Anticancer Plant Secondary Metabolites Evicting Linker Histone H1.2 from Chromatin Activate Type I Interferon Signaling. International journal of molecular sciences 0 39796235
2016 Role of linker histone H1c during the reprogramming of Chinese swamp buffalo (Bubalus Bubalis) embryos produced by somatic cell nuclear transfer. Reproduction, fertility, and development 0 25145348

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