Affinage

BAHCC1

BAH and coiled-coil domain-containing protein 1 · UniProt Q9P281

Length
2639 aa
Mass
280.0 kDa
Annotated
2026-06-09
19 papers in source corpus 8 papers cited in narrative 10 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAHCC1 is a dual histone-reader chromatin regulator that couples recognition of repressive and replication-associated histone marks to control gene silencing, DNA replication, and cell fate (PMID:33139953, PMID:40592879). Its BAH module directly engages H3K27me3 through a hydrophobic trimethyl-lysine-binding cage, co-localizing BAHCC1 with Polycomb-marked genes and, together with associated transcriptional corepressors, enforcing their silencing (PMID:33139953). A separate tandem Tudor domain selectively reads H4K20me1 and recruits both BAHCC1 and the MCM complex to replication origins, promoting origin activation and cell-cycle progression (PMID:40592879). In mice, a germline point mutation abolishing BAH–H3K27me3 engagement causes partial postnatal lethality, establishing the physiological importance of this reading activity (PMID:33139953). BAHCC1 acts as an oncogenic effector in acute leukemia, where it is transcriptionally induced by MLL-ENL and sustains leukemic immortalization in part by repressing the H3K27me3-marked cell-cycle inhibitor Cdkn1c (PMID:33139953, PMID:38452334), and in melanoma, where it associates with BRG1-containing remodeling complexes at E2F/KLF-dependent cell-cycle and DNA-repair gene promoters (PMID:37924516). It is also required for early neuronal commitment and chromatin accessibility during differentiation (PMID:32969152).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 Medium

    Before any molecular function was known, in vivo loss-of-function was needed to show BAHCC1 has a non-redundant developmental role; knockout established this.

    Evidence Gene-targeted knockout of the mouse Bahcc1 homolog (KIAA1447) with phenotypic characterization

    PMID:16807365

    Open questions at the time
    • No molecular mechanism linked to the motor phenotype
    • No chromatin or histone-reading function identified at this stage
  2. 2013 Low

    To explain BAHCC1's chromatin association, domain analysis predicted a previously hidden reader module, framing the protein as a candidate histone reader.

    Evidence Computational hydrophobic cluster analysis, PSI-BLAST, and HHpred profile comparison predicting a tandem Tudor domain

    PMID:23677940

    Open questions at the time
    • Computational prediction with no experimental validation in this work
    • Ligand specificity of the predicted domain unknown
    • No binding or structural data
  3. 2020 High

    The central question of what histone mark BAHCC1 reads and what that accomplishes was answered: the BAH module reads H3K27me3 to enforce Polycomb silencing, with corepressor recruitment and an oncogenic role in leukemia.

    Evidence Structural/biochemical binding assays, active-site mutagenesis, ChIP-seq, Co-IP with corepressors, and depletion in leukemia cell lines

    PMID:33139953

    Open questions at the time
    • Identity of the specific corepressor complexes only partially defined
    • Mechanism converting H3K27me3 reading into stable silencing not fully resolved
  4. 2020 High

    Whether BAH–H3K27me3 reading matters in the whole organism was tested by a separation-of-function knock-in, linking the reader activity directly to developmental viability.

    Evidence Germline knock-in mouse carrying a point mutation abolishing H3K27me3 binding, with survival analysis

    PMID:33139953

    Open questions at the time
    • Tissues and gene programs responsible for lethality not pinpointed
    • Does not address the replication-associated Tudor function
  5. 2020 Medium

    To place BAHCC1 in cell-fate control, its role in differentiation was probed, showing it is required for neuronal commitment and global chromatin accessibility.

    Evidence RNAi depletion in differentiating mESCs with RNA-seq, ATAC-seq, and Hi-C spatial contact analysis (Reno1 lncRNA locus)

    PMID:32969152

    Open questions at the time
    • Mechanism connecting BAHCC1 to H3K4me3-marked accessibility unclear
    • Functional role of Reno1–Bahcc1 spatial contacts not mechanistically dissected
  6. 2023 Medium

    How BAHCC1 drives a non-leukemic cancer was addressed, identifying its association with BRG1 remodeling complexes at cell-cycle and DNA-repair gene promoters and a synthetic vulnerability with PARP inhibition.

    Evidence ChIP-seq co-occupancy, Co-IP for BAHCC1–BRG1 association, knockdown with proliferation/DNA repair assays, and tumor engraftment in melanoma

    PMID:37924516

    Open questions at the time
    • Whether BAHCC1 recruits BRG1 or vice versa not established
    • Single lab; reciprocal complex-membership validation limited
  7. 2024 Medium

    The upstream driver and downstream target of BAHCC1 in MLL-rearranged leukemia were defined, showing MLL-ENL induces Bahcc1 which represses Cdkn1c to sustain immortalization.

    Evidence ChIP for MLL-ENL at the Bahcc1 promoter, shRNA depletion, Cdkn1c expression analysis, and bone marrow transplantation leukemia model

    PMID:38452334

    Open questions at the time
    • Additional repressed targets beyond Cdkn1c not enumerated
    • Single lab
  8. 2024 Medium

    A distinct, non-chromatin signaling role was reported in retinal cells, placing BAHCC1 in a TMEM97→BAHCC1→NFκB pro-inflammatory cascade.

    Evidence TMEM97 knockout/overexpression in ARPE19 cells, Co-IP, BAHCC1 siRNA, NFκB western blotting, and a Tmem97-/- mouse retinal degeneration model

    PMID:38290642

    Open questions at the time
    • Mechanism by which BAHCC1 activates NFκB unclear
    • Relationship of this cytoplasmic-signaling role to its chromatin-reading functions undefined
    • Single lab
  9. 2025 High

    The function of the second reader module was resolved: the tandem Tudor domain reads H4K20me1 to recruit the MCM complex to origins, assigning BAHCC1 a direct role in DNA replication.

    Evidence Structural analysis of the TTD–H4K20me1 complex, Co-IP/MS identifying MCM, ChIP-seq at origins, and TTD mutagenesis with replication and cell-cycle readouts

    PMID:40592879

    Open questions at the time
    • How the two reader modules are coordinated within one protein is unknown
    • Whether replication and silencing functions occur in the same cellular contexts unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how BAHCC1 integrates its repressive H3K27me3-reading, replication-promoting H4K20me1-reading, and cytoplasmic NFκB-signaling activities into a unified cellular program.
  • No structure of full-length BAHCC1 showing both reader modules
  • No model coordinating silencing versus replication roles
  • Context determinants selecting each activity not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0042393 histone binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-69306 DNA Replication 1
Partners
BRG1MCMTMEM97

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 The BAH module of BAHCC1 (BAHCC1BAH) directly recognizes and binds H3K27me3 through a hydrophobic trimethyl-L-lysine-binding 'cage', mediating co-localization of BAHCC1 with H3K27me3-marked genes and enforcing transcriptional silencing of those genes in mammalian cells. Biochemical binding assays, crystal/structural analysis, active-site mutagenesis, ChIP-seq, and knockdown/depletion experiments with gene expression readouts Nature genetics High 33139953
2020 BAHCC1 interacts with transcriptional corepressors, and in acute leukemia cells its depletion or disruption of the BAHCC1BAH–H3K27me3 interaction causes derepression of H3K27me3-targeted tumor suppressor and differentiation genes, suppressing oncogenesis. Co-immunoprecipitation (interaction with corepressors), shRNA/CRISPR depletion, RNA-seq gene expression analysis, and colony/proliferation assays in leukemia cell lines Nature genetics High 33139953
2020 Germline mutation in mice disrupting Bahcc1's H3K27me3 engagement causes partial postnatal lethality, establishing a role for BAHCC1 BAH–H3K27me3 reading in developmental viability. Gene-targeted knock-in mouse model with germline point mutation abolishing H3K27me3 binding; survival analysis of offspring Nature genetics High 33139953
2025 An evolutionarily conserved tandem Tudor domain (TTD) in BAHCC1 selectively reads H4K20me1, promotes recruitment of BAHCC1 and the MCM (Mini-chromosome Maintenance) complex to replication origin sites, and facilitates replication origin activation and DNA replication. Depletion of BAHCC1 or disruption of the BAHCC1TTD–H4K20me1 interaction reduces H4K20me1 levels and MCM loading, causing defects in replication origin activation and cell cycle progression. Biochemical binding assays, structural analysis of BAHCC1TTD–H4K20me1 complex, Co-IP/mass spectrometry identifying MCM as interacting partner, ChIP-seq/genomic analyses at replication origins, CRISPR/siRNA depletion with cell cycle and DNA replication readouts, mutagenesis of TTD disrupting H4K20me1 binding Nature communications High 40592879
2024 MLL-ENL upregulates Bahcc1 by binding to its promoter, and Bahcc1 in turn mediates MLL-ENL-driven leukemic immortalization at least partly through repression of the H3K27me3-marked cell cycle inhibitor Cdkn1c. Depletion of Bahcc1 suppresses MLL-ENL leukemogenic activity in bone marrow transplantation models. ChIP assay (MLL-ENL binding to Bahcc1 promoter), shRNA-mediated depletion of Bahcc1, gene expression analysis of Cdkn1c, bone marrow transplantation leukemia model Blood advances Medium 38452334
2024 TMEM97 positively regulates BAHCC1 expression in retinal pigment epithelium (RPE) cells, and BAHCC1 in turn promotes pro-inflammatory cytokine expression (IL1β, CCL2) via NFκB (p50, p52, p65). Co-immunoprecipitation demonstrated a physical association between TMEM97 and BAHCC1 proteins. TMEM97 knockout ARPE19 cells and overexpression, transcriptomic analysis, Co-IP, BAHCC1 siRNA silencing, NFκB western blotting, in vivo Tmem97-/- mouse retinal degeneration model with immunofluorescence Cellular signalling Medium 38290642
2023 In melanoma cells, BAHCC1 associates with BRG1-containing chromatin remodeling complexes at the promoters of E2F/KLF-dependent cell-cycle and DNA-repair genes, regulating their expression. BAHCC1 silencing leads to decreased cell proliferation and delayed DNA repair, and BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. ChIP-seq (BAHCC1 and BRG1 co-occupancy at gene promoters), Co-IP (BAHCC1–BRG1 association), siRNA/shRNA knockdown with proliferation assays, DNA damage repair assays, and tumor engraftment experiments Cell reports Medium 37924516
2020 Loss of Bahcc1 in mouse embryonic stem cells leads to early arrest in neuronal commitment, failure to induce a neuronal gene expression program, and global reduction in chromatin accessibility at regions marked by H3K4me3 at the onset of differentiation. The Reno1 lncRNA locus forms increasing spatial contacts with Bahcc1 during neurogenesis, forming a regulatory circuit required for neuronal commitment. RNAi knockdown of Bahcc1 and Reno1 in differentiating mESCs, RNA-seq, ATAC-seq (chromatin accessibility), Hi-C/3C spatial contact analysis EMBO reports Medium 32969152
2006 Targeted disruption of the mouse homolog of KIAA1447 (Bahcc1) causes hind leg motor dysfunction, establishing a developmental role for Bahcc1 in motor function in vivo. Gene-targeted knockout mouse generation and phenotypic characterization FASEB journal Medium 16807365
2013 Computational/structural analysis identified a hidden tandem Tudor domain within human BAHCC1, predicting a histone-reading function consistent with the protein's chromatin association. Hydrophobic cluster analysis (HCA) combined with PSI-BLAST domain architecture analysis and HHpred profile-profile comparison Bioinformatics Low 23677940

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Polycomb Gene Silencing Mechanisms: PRC2 Chromatin Targeting, H3K27me3 'Readout', and Phase Separation-Based Compaction. Trends in genetics : TIG 131 33494958
2020 BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis. Nature genetics 80 33139953
2012 Gene deletions and amplifications in human hepatocellular carcinomas: correlation with hepatocyte growth regulation. The American journal of pathology 66 22326833
2016 Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 40 27485686
2013 Identification of hidden relationships from the coupling of hydrophobic cluster analysis and domain architecture information. Bioinformatics (Oxford, England) 26 23677940
2006 A gene-targeting approach for functional characterization of KIAA genes encoding extremely large proteins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 16807365
2018 Choline ameliorates adult learning deficits and reverses epigenetic modification of chromatin remodeling factors related to adolescent nicotine exposure. Neurobiology of learning and memory 18 30099202
2016 TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy. Journal of human genetics 15 27928163
2013 Population genetic studies revealed local adaptation in a high gene-flow marine fish, the small yellow croaker (Larimichthys polyactis). PloS one 15 24349521
2020 Regulation of neuronal commitment in mouse embryonic stem cells by the Reno1/Bahcc1 locus. EMBO reports 14 32969152
2023 Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability. Cell reports 13 37924516
2022 Methylome Analysis in Nonfunctioning and GH-Secreting Pituitary Adenomas. Frontiers in endocrinology 13 35432200
2021 MLL1 is required for maintenance of intestinal stem cells. PLoS genetics 13 34860830
2024 Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects. BMC genomics 8 38454350
2024 Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression. Cellular signalling 3 38290642
2023 Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment. Children (Basel, Switzerland) 3 37508616
2024 Bahcc1 is critical for the aberrant epigenetic program in a mouse model of MLL-ENL-mediated leukemia. Blood advances 2 38452334
2024 Introducing effective genes in lymph node metastasis of breast cancer patients using SHAP values based on the mRNA expression data. PloS one 2 39150915
2025 BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication. Nature communications 1 40592879

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