Affinage

BAHD1

Bromo adjacent homology domain-containing 1 protein · UniProt Q8TBE0

Length
780 aa
Mass
84.7 kDa
Annotated
2026-06-09
12 papers in source corpus 8 papers cited in narrative 8 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

BAHD1 is a nuclear chromatin-repressive factor that nucleates heterochromatin and transcriptional silencing at Polycomb-regulated loci (PMID:19666599, PMID:33823544). Its BAH domain directly reads the repressive histone mark H3K27me3, and this recognition is required to target BAHD1 to chromatin and to silence H3K27me3-demarcated Polycomb targets; disrupting the BAH–H3K27me3 interaction increases histone acetylation at these loci and is embryonic-lethal in mice (PMID:33823544). Once recruited, BAHD1 assembles a multiprotein corepressor complex—directing HP1 to nuclear sites and recruiting MBD1, HDAC5, MIER1/MIER3, HDAC1/2, and PRC2—to drive histone deacetylation and formation of large H3K27me3-enriched heterochromatic domains, thereby repressing target genes including IGF2, ESR1, and PGR (PMID:19666599, PMID:26938916, PMID:33156908). Through this activity BAHD1 governs developmental and metabolic programs, with Bahd1 knockout causing placental growth restriction and altered steroid/lipid metabolism (PMID:26938916), and it represses interferon-stimulated genes downstream of IFN-λ, an immune silencing function antagonized by direct binding of the Listeria nucleomodulin LntA, which contacts BAHD1 via a dilysine motif to block its recruitment to ISG loci (PMID:21252314, PMID:24449750). BAHD1 abundance is controlled by FBXO11-mediated ubiquitin-proteasomal degradation, which during erythroid maturation clears BAHD1 from bivalent promoters to permit GATA1 recruitment and erythroid gene activation (PMID:33156908).

Mechanistic history

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

    Established BAHD1 as a heterochromatinization factor, defining its core corepressor partners and showing the BAH domain links it to H3K27me3-marked chromatin and CpG-rich promoter silencing.

    Evidence Co-IP, immunofluorescence/EM, genome-wide microarray of knockdown cells, ChIP, and domain-mutant overexpression in human cells

    PMID:19666599

    Open questions at the time
    • Did not establish whether the BAH domain binds H3K27me3 directly versus via complex members
    • Mechanism connecting heterochromatin formation to DNA methylation not addressed
  2. 2011 High

    Revealed an immune-silencing role by showing the BAHD1 complex represses interferon-stimulated genes downstream of IFN-λ and is targeted by the Listeria nucleomodulin LntA, framing BAHD1 as a host chromatin target of a bacterial effector.

    Evidence Listeria infection assays (WT vs. ΔlntA), ChIP, Bahd1(+/-) mouse infection model, and Co-IP

    PMID:21252314

    Open questions at the time
    • Structural basis of the LntA-BAHD1 interaction not yet defined
    • Scope of physiological ISGs controlled by BAHD1 not fully mapped
  3. 2014 High

    Defined the molecular interface of LntA antagonism, mapping a dilysine motif on LntA to a proline-rich region of BAHD1 and validating that this contact is required for LntA-mediated derepression of interferon responses.

    Evidence 2.2-Å crystal structure of an LntA mutant, site-directed mutagenesis, in vitro binding, and infection/transfection in human cells

    PMID:24449750

    Open questions at the time
    • No structure of the BAHD1 region engaged by LntA
    • Does not address how LntA binding sterically or allosterically blocks chromatin recruitment
  4. 2015 Medium

    Connected BAHD1-driven heterochromatin to DNA methylation patterning, showing overexpression reprograms autosomal and X-chromosomal methylation in large domains overlapping lamina-associated regions.

    Evidence Whole-genome bisulfite sequencing of isogenic HEK293 cells with stable BAHD1 overexpression vs. control

    PMID:26648976

    Open questions at the time
    • Single primary method from one lab
    • Causal mechanism linking BAHD1 to DNA methyltransferase activity not demonstrated
    • Overexpression context may not reflect endogenous patterning
  5. 2016 High

    Expanded the BAHD1 corepressor complex by identifying MIER1/MIER3 as a partner hub bridging HDAC1/2 and methyltransferases, and tied BAHD1 to hormone-receptor gene repression and to systemic metabolic and placental phenotypes in vivo.

    Evidence Co-purification/mass spectrometry, Bahd1 knockout mouse phenotyping, transcriptomics, and ChIP

    PMID:26938916

    Open questions at the time
    • Stoichiometry and assembly order of the complex not resolved
    • Direct enzymatic contribution of the associated methyltransferases not defined
  6. 2021 High

    Demonstrated that the BAH domain directly reads H3K27me3 and that this recognition is functionally required, linking the reader activity to repression of Polycomb targets and to embryonic viability.

    Evidence BAH-domain point mutagenesis, ChIP, histone modification profiling, and an H3K27me3-binding-defective knock-in mouse

    PMID:33823544

    Open questions at the time
    • Atomic structure of the BAH-H3K27me3 complex not reported here
    • Relationship between H3K27me3 reading and the previously observed DNA methylation changes not addressed
  7. 2021 High

    Identified post-translational control of BAHD1 by FBXO11-mediated degradation and showed BAHD1 physically associates with PRC2, establishing that timely BAHD1 clearance from bivalent promoters licenses GATA1-driven erythroid gene activation.

    Evidence FBXO11 knockout erythroblasts, BAHD1-PRC2 Co-IP, ChIP for BAHD1 and GATA1, and BAHD1/PRC2 depletion rescue experiments

    PMID:33156908

    Open questions at the time
    • Degron and ubiquitination sites on BAHD1 not mapped
    • Whether FBXO11 control of BAHD1 operates outside erythropoiesis unknown
  8. 2024 Medium

    Implicated BAHD1 in cancer radioresistance, showing it sustains H3K9me3/H3K27me3 heterochromatin compaction and supports double-strand break repair selectively in radioresistant cells.

    Evidence siRNA knockdown, clonogenic survival assays, and histone-mark immunoblotting in radioresistant vs. wild-type isogenic cell lines

    PMID:39719436

    Open questions at the time
    • Mechanism linking BAHD1 to H3K9me3 (versus its established H3K27me3 reading) not defined
    • Single-lab, knockdown-only evidence without in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BAHD1-templated heterochromatin is mechanistically coupled to de novo DNA methylation and H3K9me3 deposition, and the high-resolution structural basis of its BAH-H3K27me3 reading, remain unresolved.
  • No atomic structure of BAHD1 BAH domain bound to H3K27me3
  • Enzyme(s) BAHD1 recruits to write DNA methylation not identified
  • Direct mechanistic link between BAHD1 and H3K9me3 unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2
Partners
FBXO11HDAC1HDAC5HP1MBD1MIER1MIER3PRC2
Complex memberships
BAHD1 chromatin-repressive complexPRC2 (associated)

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 BAHD1 is a nuclear heterochromatinization factor that interacts with HP1, MBD1, HDAC5, and the transcription factor SP1. Overexpression directs HP1 to specific nuclear sites, promotes formation of large heterochromatic domains enriched in H3K27me3 and lacking acetyl-H4. The BAH domain is required for BAHD1 colocalization with H3K27me3. BAHD1 represses target genes (including IGF2) by recruiting MBD1 and HDAC5 to CpG-rich promoters. Co-immunoprecipitation, immunofluorescence/electron microscopy, genome-wide microarray of knockdown cells, ChIP, overexpression studies with domain mutants Proceedings of the National Academy of Sciences of the United States of America High 19666599
2011 The secreted Listeria monocytogenes virulence factor LntA targets BAHD1 in the host cell nucleus. The BAHD1-chromatin-associated complex represses interferon-stimulated genes (ISGs) downstream of IFN-λ; LntA prevents BAHD1 recruitment to ISG loci and thereby stimulates their expression, modulating IFN-λ-mediated immune response. Bacterial infection assays (wild-type vs. ΔlntA Listeria), chromatin immunoprecipitation, BAHD1(+/-) mouse infection model, co-immunoprecipitation Science (New York, N.Y.) High 21252314
2014 LntA inhibits BAHD1 through a direct protein–protein interaction: a dilysine motif (K180/K181) in the elbow region of LntA contacts a central proline-rich region of BAHD1. Mutation of K180/K181 abolishes LntA recruitment to BAHD1-associated nuclear foci and abrogates LntA-mediated stimulation of interferon responses during infection. Crystal structure of the K180D/K181D mutant at 2.2-Å resolution reveals redistribution of surface charges near a groove implicated in target recognition. Crystal structure determination (2.2 Å), site-directed mutagenesis, in vitro binding assays, transfection/infection experiments in human cells mBio High 24449750
2016 BAHD1 forms a multiprotein chromatin-repressive complex containing MIER1, MIER3, histone deacetylases (HDAC1/2), and methyltransferases. MIER proteins are novel BAHD1 partners; BAHD1-MIER interaction acts as a hub for these epigenetic regulators. BAHD1 and MIER1/3 repress estrogen receptor ESR1 and progesterone receptor PGR gene expression, and BAHD1 overexpression increases MIER1 enrichment on the inactive X chromosome. Bahd1 knockout in mice causes placental growth restriction, hypocholesterolemia, hypoglycemia, and altered steroid/lipid metabolism gene expression. Biochemical co-purification/mass spectrometry of BAHD1-associated complex, Bahd1 knockout mouse phenotyping, transcriptome profiling (microarray), ChIP, stable overexpression cell lines PLoS genetics High 26938916
2021 The BAH domain of BAHD1 directly reads H3K27me3; this interaction is required for overall BAHD1 targeting to chromatin and for optimal repression of H3K27me3-demarcated Polycomb target genes. Point mutations disrupting BAH–H3K27me3 binding lead to increased histone acetylation at Polycomb targets. Mice carrying the H3K27me3-interaction-defective Bahd1BAH mutation show marked embryonic lethality. Point mutagenesis of BAH domain, chromatin immunoprecipitation, histone modification profiling, knock-in mouse model Nucleic acids research High 33823544
2021 The E3 ubiquitin ligase FBXO11 targets BAHD1 for proteolysis during erythroid maturation. BAHD1 is an H3K27me3 reader that recruits transcriptional corepressors and physically interacts with PRC2. Loss of FBXO11 causes BAHD1 accumulation at bivalent gene promoters, preventing GATA1 recruitment and blocking erythroid gene activation. Depletion of either BAHD1 or PRC2 restores erythroid gene expression in FBXO11-/- cells. FBXO11 knockout erythroblasts, co-immunoprecipitation of BAHD1-PRC2 complex, ChIP for BAHD1 and GATA1 at target promoters, rescue experiments (BAHD1/PRC2 depletion) Blood High 33156908
2015 BAHD1 overexpression in HEK293 cells induces de novo DNA methylation at autosomes (predominantly at satellites, interspersed repeats, and intergenic regions) and causes hypomethylation on the X chromosome (at gene bodies and enhancers), organized in large chromosomal domains overlapping lamina-associated domains, linking BAHD1-mediated heterochromatin formation to DNA methylation patterning. Whole-genome bisulfite sequencing (BS-seq) comparing isogenic HEK293 cells with stable BAHD1 overexpression vs. control Frontiers in genetics Medium 26648976
2024 BAHD1 contributes to heterochromatin compaction (H3K9me3 and H3K27me3) in radioresistant cancer cells; siRNA knockdown of BAHD1 preferentially reduces H3K9me3 and H3K27me3 in radioresistant but not wild-type cells, reverses radioresistance in clonogenic assays, and reduces DNA double-strand break repair. siRNA knockdown, clonogenic survival assays, histone modification immunoblotting (H3K9me3, H3K27me3), comparison of radioresistant vs. wild-type isogenic cell lines Cell death & disease Medium 39719436

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science (New York, N.Y.) 139 21252314
2009 Human BAHD1 promotes heterochromatic gene silencing. Proceedings of the National Academy of Sciences of the United States of America 73 19666599
2014 Structural basis for the inhibition of the chromatin repressor BAHD1 by the bacterial nucleomodulin LntA. mBio 34 24449750
2021 FBXO11-mediated proteolysis of BAHD1 relieves PRC2-dependent transcriptional repression in erythropoiesis. Blood 31 33156908
2016 Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism. PLoS genetics 29 26938916
2021 A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing. Nucleic acids research 25 33823544
2015 Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome. Frontiers in genetics 18 26648976
2015 Computational Prediction and Validation of BAHD1 as a Novel Molecule for Ulcerative Colitis. Scientific reports 17 26183847
2018 Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders. Journal of medical genetics 14 30352868
2022 BAHD1 serves as a critical regulator of breast cancer cell proliferation and invasion. Breast cancer (Tokyo, Japan) 6 35048286
2020 BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice. PloS one 6 32407325
2024 Genomic and transcriptomic profiling of radioresistant prostate and head and neck cancers implicate a BAHD1-dependent modification of DNA damage at the heterochromatin. Cell death & disease 1 39719436

Missed literature

Know a paper Affinage missed for BAHD1? Flag it for the maintainers and the community.

No submissions yet.