Affinage

SMCHD1

Structural maintenance of chromosomes flexible hinge domain-containing protein 1 · UniProt A6NHR9

Length
2005 aa
Mass
226.4 kDa
Annotated
2026-06-10
92 papers in source corpus 39 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMCHD1 is a non-canonical SMC-family chromatin regulator that organizes higher-order heterochromatin architecture and enforces epigenetic silencing across the inactive X chromosome, imprinted loci, clustered gene families, and the D4Z4 macrosatellite (PMID:18425126, PMID:23754746, PMID:23819640, PMID:29887375). The protein combines an N-terminal GHKL-type ATPase module—stabilized as a dimer by a ubiquitin-like (UBL) fold and a transducer domain whose ATP hydrolysis drives selective chromatin enrichment (PMID:27059856, PMID:31312724, PMID:34109974)—with a C-terminal hinge domain that forms an unconventional coiled-coil-augmented homodimer capable of binding both DNA and RNA (PMID:26091879, PMID:26733688). SMCHD1 is loaded onto H3K9me-modified chromatin through an LRIF1–HP1 interaction and onto the inactive X via the Xist–HNRNPK–PRC1–H2AK119ub pathway, where it acts downstream of Polycomb to merge A/B chromatin compartments into the Xi's distinctive compartment-less, TAD-attenuated architecture and to build H3K9me3 heterochromatin blocks anchored at the nuclear lamina (PMID:26391951, PMID:29887375, PMID:30428357, PMID:31270318, PMID:40715155). Functionally it compacts chromatin, antagonizes CTCF and PRC2, facilitates CpG methylation and opposes TET-mediated 5mC oxidation at its targets, and maintains monoallelic expression at imprinted clusters and Hox genes as a maternal-effect regulator (PMID:26091879, PMID:30127357, PMID:33523915, PMID:33186096, PMID:35739109). At D4Z4, loss of SMCHD1 repressor activity causes hypomethylation and derepression of DUX4, defining SMCHD1 as the FSHD2 disease gene and a modifier of FSHD1 severity (PMID:23143600, PMID:24075187, PMID:26575099), while distinct ATPase-domain mutations with gain-of-function character cause Bosma arhinia microphthalmia syndrome (BAMS) (PMID:28067911, PMID:29748383). SMCHD1 additionally promotes 53BP1-dependent NHEJ at DNA double-strand breaks and uncapped telomeres (PMID:25294876, PMID:32080884).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2008 High

    Establishing that SMCHD1 is required to maintain X inactivation but not Xist expression defined it as an epigenetic maintenance factor acting downstream of the silencing trigger.

    Evidence ENU mutagenesis screen with female-specific lethality, Xi immunolocalization, and X-linked CpG methylation assay in mice

    PMID:18425126

    Open questions at the time
    • No molecular mechanism for Xi targeting
    • Domain architecture and biochemical activity unknown
  2. 2012 High

    Human genetics and knockdown linked SMCHD1 loss to D4Z4 hypomethylation and DUX4 derepression and extended its silencing role to autosomal imprinted and clustered loci, establishing it as a disease gene and broad epigenetic modifier.

    Evidence Genetic linkage in FSHD2 kindreds plus knockdown with DUX4 readout, and genome-wide expression/bisulfite analysis in Smchd1 mutant mouse cells

    PMID:23143600 PMID:23754746

    Open questions at the time
    • Mechanism of CpG island methylation control unresolved
    • Direct vs indirect target binding not yet shown
  3. 2013 High

    Imaging, ChIP, and allele-specific assays showed SMCHD1 directly binds D4Z4, compacts the Barr body via a PRC2-independent HP1-binding partner, and enforces monoallelic imprinted expression downstream of the primary methylation imprint.

    Evidence RNAi depletion with Xi compaction imaging and Co-IP (HBiX1), ChIP at D4Z4 in FSHD1 myotubes, and allele-specific RNA-seq/SNP analysis in mutant mice

    PMID:23542155 PMID:23819640 PMID:24075187

    Open questions at the time
    • Biochemical basis of compaction not defined
    • How SMCHD1 reaches autosomal targets unclear
  4. 2014 Medium

    Discovery of SMCHD1 accumulation at DNA double-strand breaks and its 53BP1-regulated promotion of NHEJ over HR established a genome-stability role distinct from epigenetic silencing.

    Evidence Laser micro-irradiation with live imaging and co-localization, plus NHEJ/HR repair assays and foci analysis in SMCHD1-deficient/knockout cells

    PMID:24790221 PMID:25294876

    Open questions at the time
    • Single labs, not independently replicated
    • Mechanism of recruitment to breaks beyond 53BP1 unknown
  5. 2015 High

    Biochemistry and genome-wide ChIP defined the two functional modules—a DNA/RNA-binding hinge homodimer and an active GHKL-ATPase dimer—and the LRIF1–HP1γ loading route at H3K9me3 chromatin, with SMCHD1 acting antagonistically to CTCF.

    Evidence Hinge-domain DNA/RNA binding assays with ChIP-seq, and EM, ATPase assay, and Co-IP with LRIF1/HP1γ

    PMID:26091879 PMID:26391951

    Open questions at the time
    • Parallel Xi loading pathway not yet molecularly defined
    • How ATPase activity couples to chromatin function unknown
  6. 2016 High

    Reconstitution and SAXS characterized the N-terminal GHKL-ATPase as a radicicol/ADP-sensitive monomeric enzyme and the hinge as an unconventional coiled-coil homodimer, with an FSHD mutation compromising stability.

    Evidence Recombinant ATPase assays with inhibitor pharmacology and disease-mutant stability tests, and SAXS of the hinge domain

    PMID:26733688 PMID:27059856

    Open questions at the time
    • Hinge structure lacked mutagenesis validation
    • Oligomeric state of full-length protein unresolved
  7. 2017 High

    Identification of ATPase-domain mutations in BAMS, behaving as gain-of-function alleles unlike loss-of-function FSHD2 mutations, revealed an allelic series with opposing functional consequences.

    Evidence Proband sequencing, zebrafish CRISPR, transcriptomics, and Xenopus in vivo plus biochemical ATPase tests

    PMID:28067911

    Open questions at the time
    • Mechanism connecting altered ATPase to craniofacial phenotype unclear
    • Tissue specificity of the two disorders unexplained
  8. 2018 High

    Hi-C and chromatin profiling established SMCHD1 as an architectural factor that merges A/B and S1/S2 compartments into the compartment-less Xi and limits short-range/TAD interactions and ectopic enhancer activation genome-wide, downstream of the Xist-HNRNPK-PRC1-H2AK119ub pathway.

    Evidence Allele-specific Hi-C, RNA FISH, and ChIP-seq/ATAC-seq in knockout cells, plus RIP showing no specific RNA binding and H2AK119ub-dependent localization

    PMID:29887375 PMID:30071896 PMID:30127357 PMID:30428357

    Open questions at the time
    • Causal link between architecture and silencing not yet dissociated
    • Domain requirements for compaction in vivo incomplete
  9. 2019 High

    Epistasis dissection placed SMCHD1 in an obligatory sequential cascade with Xist and PRC1 in Xi folding, established its antagonism of TADs/A-B compartments, defined the UBL domain and structure of the ATPase dimer, and extended its roles to D4Z4 de novo methylation and embryonic genome activation.

    Evidence Allelic Hi-C with component depletions and RNA FISH, crystal structure of the ATP-bound N-terminal module with disease mutants, reprogramming/bisulfite assays, and siRNA in two-cell embryos

    PMID:30604745 PMID:30698748 PMID:31270318 PMID:31312724 PMID:31365290

    Open questions at the time
    • Catalytic cycle coupling to chromatin loading not defined
    • Embryonic and reprogramming roles from single labs
  10. 2020 High

    SMCHD1 was shown to act upstream of ATM signaling at uncapped telomeres, to complex with and restrain TET enzymes, and to function as a maternal-effect gene for genomic imprinting downstream of Polycomb.

    Evidence Telomere uncapping with fusion/overhang/ATM-signaling assays and genetic epistasis; Co-IP, 5hmC quantification and quadruple-knockout epistasis; and maternal-zygotic conditional knockout with allele-specific expression

    PMID:32080884 PMID:33186096 PMID:33523915

    Open questions at the time
    • Direct vs indirect TET inhibition mechanism unclear
    • How SMCHD1 is positioned upstream of ATM not structurally defined
  11. 2021 Medium

    Functional mapping established the UBL domain as essential for ATPase dimerization and chromatin localization, and interactome proteomics identified RUVBL1 and EZHIP as partners modulating DUX4 repression and PRC2 activity.

    Evidence Biophysical dimerization and ATPase assays with UBL deletion and fractionation; quantitative MS interactome with RUVBL1 loss-of-function and EZHIP Co-IP

    PMID:34109974 PMID:34880314

    Open questions at the time
    • Interactome partners largely not functionally validated
    • How UBL-dependent dimerization drives chromatin engagement unresolved
  12. 2022 Medium

    SMCHD1 was shown to build Xi H3K9me3 blocks and confine H3K27me3, and to act downstream of parallel SPEN and Polycomb silencing pathways during differentiation, refining its position in the X-inactivation hierarchy.

    Evidence H3K9me3/H3K27me3 ChIP-seq in deficient stem cells and fibroblasts, and SPEN separation-of-function plus SmcHD1 depletion silencing assays

    PMID:35584662 PMID:35831949

    Open questions at the time
    • Mechanism of H3K9me3 block formation unknown
    • Single-lab ChIP datasets
  13. 2023 High

    A knock-in gain-of-function mutation dissociated SMCHD1's role in long-range chromatin folding from gene silencing, while LRIF1 was confirmed as the converging effector at D4Z4 and the LRIF1 promoter, and maternal haploinsufficiency was tied to Hox mis-patterning.

    Evidence Point-mutation knock-in mice with Hi-C/ChIP-seq/RNA-seq; ChIP and somatic CRISPR KO at D4Z4 and LRIF1 promoter; and zebrafish/mouse Smchd1 and Lrif1 knockouts with patient fibroblast validation

    PMID:35739109 PMID:37380887 PMID:37749075

    Open questions at the time
    • How silencing is achieved independent of architecture unresolved
    • LRIF1 interdependency differs across loci by unknown mechanism
  14. 2024 Medium

    Newer functions emerged: SMCHD1 controls DNMT3B alternative splicing via RBM5 recruitment, acts as an enhancer co-activator for cell-cycle genes, restricts herpesviruses and AAV via LRIF1-HP1-dependent genome binding, and is SUMOylated to modulate repressor interactions.

    Evidence Splicing screens and RNA-IP (RBM5); enhancer ChIP-seq with LAP2 rescue; CRISPR screens with viral-genome ChIP and DNA-binding mutants; and SUMO-site mapping with Co-IP (preprint)

    PMID:37010434 PMID:38809976 PMID:38976714 PMID:38994563

    Open questions at the time
    • Each role from a single lab
    • Mechanistic integration with core chromatin function unclear
  15. 2025 High

    Multi-omic and single-molecule/reconstitution studies positioned SMCHD1 as a nuclear-lamina anchor for heterochromatin and showed LRIF1- and ATP-dependent chromatin enrichment with direct ATP-independent DNA bridging/compaction by the full-length homodimer.

    Evidence Hi-C/ChIP-seq/WGBS/ATAC-seq in knockout myoblasts; and single-molecule imaging with ATPase mutants and reconstituted DNA-compaction assays (two preprints)

    PMID:40715155

    Open questions at the time
    • Reconstitution/imaging findings are preprints
    • How ATP hydrolysis selects target sites while opposing compaction in vitro not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ATPase/hinge homodimer integrates target selection, compaction, compartment merging, and silencing—and why distinct ATPase-altering mutations produce FSHD2 versus BAMS—remains unresolved.
  • No structure of full-length protein on chromatin
  • Causal chain from ATP hydrolysis to silencing undefined
  • Mechanistic basis of opposing disease alleles incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0016787 hydrolase activity 3 GO:0140110 transcription regulator activity 3 GO:0140657 ATP-dependent activity 3 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 2
Partners
EZHIPHNRNPKHP1ΓLRIF1RBM5RUVBL1TET1TRIM28
Complex memberships
SMCHD1-LRIF1-HP1 complexSMCHD1-TET complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 SmcHD1 localizes to the inactive X chromosome and is required for maintenance of X inactivation and hypermethylation of CpG islands on the inactive X; it is not required for correct Xist expression. ENU mutagenesis screen, homozygous female-specific lethality analysis, X-linked gene methylation assay, immunofluorescence localization Nature genetics High 18425126
2012 SMCHD1 mutations reduce SMCHD1 protein levels and cause genome-wide D4Z4 CpG hypomethylation; SMCHD1 acts as an epigenetic modifier of the D4Z4 metastable epiallele, and its loss leads to D4Z4 contraction-independent DUX4 expression in skeletal muscle. Genetic linkage in human kindreds, SMCHD1 knockdown in skeletal muscle cells, D4Z4 methylation assay, DUX4 expression analysis Nature genetics High 23143600
2012 Smchd1 is required for CpG island methylation and silencing of ~10% of inactive X genes and for CpG island methylation at the Prader-Willi syndrome imprinted locus and protocadherin-alpha and -beta clusters on autosomes; silenced genes occur in non-random clusters. Genome-wide expression analysis (RNA-seq/microarray) in Smchd1 mutant mouse cells, bisulfite methylation analysis Molecular and cellular biology High 23754746
2013 SMCHD1 compacts the inactive X chromosome (Barr body) through a PRC2-independent pathway. HBiX1 (a HP1-binding protein) is required for SMCHD1 localization to H3K9me3 domains; HBiX1 localization to XIST-H3K27me3 domains requires SMCHD1; depletion of either HBiX1 or SMCHD1 causes Xi decompaction. RNAi depletion, immunofluorescence, co-immunoprecipitation, Xi compaction imaging Nature structural & molecular biology High 23542155
2013 Smchd1 directly binds D4Z4 and suppresses somatic DUX4 expression; SMCHD1 acts as a genetic modifier of FSHD1 severity, and SMCHD1 knockdown in FSHD1 myotubes increases DUX4 expression. ChIP at D4Z4, SMCHD1 knockdown in FSHD1 myotubes, DUX4 expression assay American journal of human genetics High 24075187
2013 Smchd1 is required for monoallelic expression of imprinted genes in the Snrpn cluster and Igf2r cluster; loss of Smchd1 causes biallelic expression without disrupting the primary differential methylation imprint control region, indicating Smchd1 acts downstream of the primary imprint. Genome-wide microarray, RNA-seq, SNP analysis of allele-specific expression in Smchd1 mutant mice, bisulfite methylation Epigenetics & chromatin High 23819640
2014 SMCHD1 accumulates at DNA double-strand break sites (laser micro-irradiation) along with Ku80 and RAD51; SMCHD1-deficient cells show decreased efficiency of DNA repair and reduced cell viability after DNA damage. Laser micro-irradiation with live-cell imaging of SMCHD1 recruitment, co-localization with Ku80/RAD51, cell viability assay in SMCHD1-deficient cells Journal of cell science Medium 24790221
2014 SMCHD1 promotes non-homologous end joining (NHEJ) and inhibits homologous recombination (HR) at DNA DSBs; its recruitment to damage foci is regulated by 53BP1; loss of SMCHD1 leads to reduced 53BP1 foci, increased BRCA1 foci, less efficient NHEJ, and elevated HR. SMCHD1 knockout, γH2AX/53BP1/BRCA1 foci analysis, NHEJ and HR repair assays The Journal of biological chemistry Medium 25294876
2015 The homodimeric hinge domain of Smchd1 mediates chromatin interactions; the hinge domain can bind both DNA and RNA. Smchd1 binds cis-regulatory elements including CTCF binding sites at protocadherin clusters, where Smchd1 and CTCF act antagonistically. Genome-wide ChIP-seq, biochemical and biophysical analysis of hinge domain DNA/RNA binding, chromatin immunoprecipitation, transcriptomic analysis Proceedings of the National Academy of Sciences of the United States of America High 26091879
2015 SMCHD1 principal chromatin loading mechanism involves an LRIF1-mediated interaction with HP1γ at H3K9me3-modified chromatin. SMCHD1 forms an active GHKL-ATPase homodimer structurally resembling prokaryotic condensins by electron microscopy. A parallel loading pathway accounts for localization to the inactive X chromosome. Electron microscopy, ATPase activity assay, Co-IP with HP1γ/LRIF1, chromatin fractionation, ChIP Molecular and cellular biology High 26391951
2015 SMCHD1 protein levels at D4Z4 decline during muscle cell differentiation, correlating with DUX4 derepression. In FSHD2 (but not FSHD1), loss of SMCHD1 repressor activity is partially compensated by increased PRC2-mediated H3K27me3 at D4Z4. Moderate SMCHD1 overexpression silences DUX4 in FSHD1 and FSHD2 myotubes. ChIP-qPCR for SMCHD1 at D4Z4 during differentiation, H3K27me3 ChIP, SMCHD1 overexpression and knockdown with DUX4 expression readout Epigenetics Medium 26575099
2016 The N-terminal region of Smchd1 exists as a monomer and exhibits GHKL-type ATPase activity that can be antagonized by ADP or the Hsp90 inhibitor radicicol. An FSHD patient-derived mutation in the ATPase domain compromises protein stability. Recombinant protein expression, ATPase activity assay, inhibitor pharmacology, stability assay with disease mutant The Biochemical journal High 27059856
2016 The hinge domain of Smchd1 adopts an unconventional homodimeric arrangement augmented by an intermolecular coiled coil between two monomers, markedly different from archetypical SMC proteins, as revealed by SAXS. Small-angle X-ray scattering (SAXS) of recombinant hinge domain The Biochemical journal Medium 26733688
2017 SMCHD1 mutations in the ATPase domain cause BAMS (Bosma arhinia microphthalmia syndrome). Biochemical tests and Xenopus in vivo assays suggest BAMS mutations may behave as gain-of-function alleles, in contrast to loss-of-function FSHD2 mutations. Sequencing of arhinia probands, CRISPR/Cas9 in zebrafish, transcriptome analysis, biochemical tests (ATPase), Xenopus embryo assays Nature genetics High 28067911
2018 SMCHD1 merges A/B compartments into S1/S2 compartments and then fuses S1/S2 into a compartment-less Xi architecture. Loss of SMCHD1 results in persistent S1/S2 organization, strengthening of TADs, and regional defects in Xist spreading and heterochromatic silencing. Hi-C, allele-specific chromatin conformation analysis, RNA FISH for Xist spreading, gene expression in SMCHD1 knockout cells Cell High 29887375
2018 FSHD2- and BAMS-associated SMCHD1 missense mutations have opposing effects on ATPase activity: FSHD2 mutations only decrease ATP hydrolysis, whereas many BAMS mutations increase ATPase activity and cause decreased eye size in Xenopus. A mutation found in both disorders increases ATPase activity. In vitro ATPase activity assay of disease mutants, Xenopus craniofacial development assay The Journal of biological chemistry High 29748383
2018 Smchd1 is a novel regulator of long-range chromatin interactions; at autosomal targets (including Hox clusters), loss of Smchd1 increases short-range interactions and causes ectopic enhancer activation. On the inactive X, loss increases short-range interactions and spreads H3K27me3 into regions not normally decorated. Hi-C, ChIP-seq (H3K27me3, H3K4me1/2), ATAC-seq, RNA-seq in Smchd1 knockout mice Nature structural & molecular biology High 30127357
2018 Smchd1 localization to the inactive X requires the Xist-HnrnpK-PRC1 pathway and is H2AK119ub-dependent. Smchd1 does not bind Xist or other RNA molecules with specificity. Disruption of this interaction destabilizes Smchd1 and affects gene silencing genome-wide. RNA immunoprecipitation (RIP, showing no RNA binding), H2AK119ub depletion experiments, Xi localization imaging, genome-wide gene expression analysis Cell reports High 30428357
2018 SMCHD1 nuclear localization requires specific N-terminal regions; dimerization requires identified domains; full-length SMCHD1 undergoes protein cleavage at defined sites. SMCHD1 mutants associated with FSHD increase DUX4 expression in FSHD1 myoblasts. Lentiviral expression of Flag-tagged full-length and deletion mutants, nuclear localization assay, dimerization assay, DUX4 expression analysis Skeletal muscle Medium 30071896
2019 PRC1 drives formation of Xi-specific S1/S2 compartments via Xist RNA; SMCHD1 then merges S1/S2 to form the Xi super-structure. Loss of SMCHD1 traps Xist in the S1 compartment and impairs Xist spreading into S2. Xist, PRC1, and SMCHD1 collaborate in an obligatory sequential manner. Hi-C, Xist RNA FISH, SMCHD1/PRC1/HNRNPK depletion, allele-specific chromatin conformation analysis Nature communications High 31270318
2019 SmcHD1 is required to antagonize TAD formation and A/B compartmentalization on the inactive X; in SmcHD1 mutant cells, sub-megabase domains with gene activation and CpG hypomethylation appear, and features of active X higher-order architecture (A/B compartments, partial TAD restoration) emerge on Xi. Allelic Hi-C, allelic RNA-seq and bisulfite-seq, H3K27me3 ChIP-seq in SmcHD1 mutant cells Nature communications High 30604745
2019 SMCHD1 is involved in de novo methylation at the D4Z4 macrosatellite during reprogramming at the pluripotent stage but appears dispensable for methylation maintenance. Reprogramming assays with SMCHD1 mutant patient cells, bisulfite sequencing of D4Z4 methylation dynamics Nucleic acids research Medium 30698748
2019 The crystal structure of the human SMCHD1 N-terminal ATPase module bound to ATP reveals a functional dimer stabilized by a novel N-terminal ubiquitin-like (UBL) fold and a downstream transducer domain. FSHD2-specific mutant constructs abolish ATPase activity and/or dimerization, while BAMS mutations do not consistently do so. Crystal structure determination, in vitro ATPase activity assay, dimerization assay, disease mutant characterization Communications biology High 31312724
2019 SMCHD1 terminates the first embryonic genome activation (EGA1) event in mouse two-cell embryos; Smchd1 siRNA knockdown causes overexpression of Dux and Zscan4 in two-cell embryos, with prolonged expression through the eight-cell stage. siRNA knockdown in zygotes, quantitative expression analysis of Dux/Zscan4 in two-cell and eight-cell embryos American journal of physiology. Cell physiology Medium 31365290
2020 SMCHD1 is required for ATM-dependent DNA damage signaling and NHEJ at unprotected telomeres. Co-depletion of SMCHD1 and TRF2 reduced telomeric overhang removal and chromosome end fusions; SMCHD1-deficient cells show reduced ATM S1981 phosphorylation and diminished γH2AX and 53BP1 TIF formation, placing SMCHD1 upstream of ATM phosphorylation. SMCHD1 knockout, telomere uncapping (TRF2 depletion), overhang assay, chromosome fusion assay, ATM/γH2AX/53BP1 focus analysis, genetic epistasis with TPP1 removal The EMBO journal High 32080884
2020 SMCHD1 forms complexes with TET proteins and negatively regulates TET enzymatic activities. Loss of SMCHD1 in mouse ES cells induces DNA hypomethylation preferentially at SMCHD1 target sites, accumulation of 5hmC, and activation of Dux. In Smchd1/Tet1/Tet2/Tet3 quadruple-knockout cells, DNA demethylation and Dux activation upon SMCHD1 loss are TET-dependent. Co-immunoprecipitation of SMCHD1-TET complexes, 5hmC quantification, quadruple-knockout epistasis experiment, whole-genome bisulfite sequencing, RNA-seq Science advances High 33523915
2020 Smchd1 is a maternal effect gene required for genomic imprinting; maternal Smchd1 regulates imprinted expression of ten genes in mice without altering germline DNA methylation imprints, suggesting SMCHD1 acts downstream of polycomb imprints. Zygotic SMCHD1 also has a dose-dependent effect on imprinted expression of seven genes. Conditional maternal-zygotic knockout of Smchd1, allele-specific expression analysis, bisulfite sequencing of germline DMRs, ChIP-seq eLife High 33186096
2021 The UBL domain of SMCHD1 is required for ATPase dimerization (dependent on UBL domain and ATP binding) and for chromatin localization of full-length SMCHD1 in cells; deletion of the UBL domain disrupts chromatin interaction without affecting catalytic rate in vitro. Biophysical dimerization assay, in vitro ATPase assay, UBL deletion mutant chromatin localization analysis by cell fractionation The Biochemical journal Medium 34109974
2021 SMCHD1 interacts with 28 nuclear proteins including RUVBL1 and EZHIP; loss of RUVBL1 further derepresses DUX4 in FSHD myocytes; SMCHD1 interacts with EZHIP, which prevents global H3K27me3 deposition by PRC2. Quantitative proteomics (mass spectrometry) of SMCHD1 interactome, ChIP at D4Z4, RUVBL1 loss-of-function with DUX4 expression readout, Co-IP for EZHIP interaction Scientific reports Medium 34880314
2022 SmcHD1 underlies formation of H3K9me3-enriched blocks on the inactive X chromosome; SmcHD1 deficiency causes substantial loss of H3K9me3 blocks and aberrant redistribution of H3K27me3 on Xi, leading to derepression of X-inactivated genes. ChIP-seq for H3K9me3 and H3K27me3 in SmcHD1-deficient epiblast stem cells and mouse embryonic fibroblasts, gene expression analysis Development Medium 35831949
2022 SPEN and Polycomb pathways function in parallel (not sequentially) to establish X-linked gene silencing; differentiation-dependent recruitment of SmcHD1 is required for silencing many X-linked genes, functioning downstream of SPEN and Polycomb. SPEN separation-of-function mutation, SmcHD1 depletion, X-linked gene silencing assays during ES cell differentiation Cell reports Medium 35584662
2022 Maternal SMCHD1 haploinsufficiency causes precocious and ectopic HOX transcription; wild-type offspring of heterozygous Smchd1 knockout zebrafish mothers exhibit vertebrate patterning defects. Lrif1 (a direct SMCHD1 interacting partner) knockout phenocopies Smchd1 knockout in zebrafish. HOX mis-regulation involves aberrant DNA methylation and persists stably in cultured FSHD2 patient fibroblasts. Zebrafish and mouse Smchd1 knockout, HOX expression analysis, DNA methylation analysis, Lrif1 knockout in zebrafish, FSHD2 patient fibroblast analysis Nature communications High 35739109
2023 A gain-of-function SMCHD1 point mutation enhances silencing at developmental targets (including D4Z4/DUX4) and causes homeotic transformation in mice. Paradoxically, the mutant depletes long-range chromatin interactions similarly to SMCHD1 absence, indicating SMCHD1's role in long-range chromatin interactions is not directly linked to gene silencing. Point mutation knock-in in mice, RNA-seq, Hi-C, ChIP-seq for PRC2 and CTCF, Hox gene expression, DUX4 repression assay Nature communications High 37749075
2023 SMCHD1 and LRIF1 both converge at the D4Z4 locus and the LRIF1 promoter; SMCHD1 together with the long isoform of LRIF1 binds the LRIF1 promoter and silences LRIF1 expression. Somatic loss-of-function of either SMCHD1 or LRIF1 alone does not result in D4Z4 chromatin changes; they form an auxiliary layer of D4Z4 repression. SMCHD1 and LRIF1 interdependency differs between D4Z4 and the LRIF1 promoter. ChIP at D4Z4 and LRIF1 promoter, somatic CRISPR KO of SMCHD1/LRIF1, DUX4 and LRIF1 expression assay, allele-specific analysis Communications biology Medium 37380887
2023 SMCHD1 restricts KSHV lytic reactivation by associating with the KSHV genome (most prominently at ORI-Lyt); SMCHD1 DNA-binding-defective mutants cannot bind ORI-Lyt and fail to restrict KSHV lytic replication. SMCHD1 acts as a pan-herpesvirus restriction factor suppressing alpha, beta, and gamma herpesviruses. Genome-wide CRISPR-Cas9 screen, chromatin profiling (ChIP of SMCHD1 on viral genome), SMCHD1 DNA-binding mutants, KSHV reactivation assays, murine herpesvirus in vivo model mBio Medium 37010434
2024 SMCHD1 is a key regulator of alternative splicing; SMCHD1 loss causes mis-splicing of DNMT3B (mediated by the splicing factor RBM5, which requires SMCHD1 for recruitment), leading to DNMT3B isoform switching, D4Z4 hypomethylation, and DUX4 overexpression. RNA-seq in FSHD muscle biopsies and Smchd1 KO cells, high-throughput splicing factor screen, RNA immunoprecipitation confirming SMCHD1-RBM5 interaction, bisulfite methylation of D4Z4 Science advances Medium 38809976
2024 SMCHD1 acts as a transcriptional co-activator at enhancers of cell cycle genes in myoblasts; SMCHD1 depletion causes a DUX4-independent defect in myoblast proliferation. LAP2 was identified as a key SMCHD1 target whose ectopic expression rescues the proliferation defect. Acute SMCHD1 depletion, ChIP-seq at enhancers, RNA-seq, LAP2 rescue experiment in SMCHD1-depleted myoblasts Nucleic acids research Medium 38994563
2024 SMCHD1 represses AAV transgene expression by forming an LRIF1-HP1-containing protein complex that directly binds the AAV genome to maintain a heterochromatin-like state; disruption of this complex (SMCHD1-KO or LRIF1-KD) results in AAV transcriptional activation. Genome-wide CRISPR screen, ChIP of SMCHD1 on AAV genome, SMCHD1-KO/LRIF1-KD with AAV transgene expression readout, Co-IP of LRIF1-HP1 complex PLoS pathogens Medium 38976714
2025 SMCHD1 colocalizes with Lamin B1 and H3K9me3 at the nuclear lamina in human myoblasts. Loss of SMCHD1 causes heterochromatin and Lamin B1 depletion at the nuclear lamina, increased DNA methylation along chromosomes, loss of long-range B-compartment contacts, formation of new TADs and loops, and B-to-A compartment transitions with activation of silenced genes. SMCHD1 functions as an anchor for heterochromatin domains at the nuclear lamina. SMCHD1 knockout in human myoblasts, Hi-C, ChIP-seq (H3K9me3, Lamin B1), ATAC-seq, WGBS, RNA-seq Nature communications High 40715155
2024 SMCHD1 is SUMOylated primarily at lysine 1374; SUMOylation mediates SMCHD1 interactions with chromatin repressors TRIM28, HNRNPK, and SETDB1; SUMOylation impacts Xi engagement of SMCHD1, D4Z4 chromatin repression (preventing DUX4 expression), and LRIF1 promoter activity. SUMOylation site mapping by mass spectrometry, Co-IP in SUMO-dependent manner, Xi localization assay, D4Z4/DUX4 expression readout, LRIF1 promoter assay bioRxivpreprint Medium
2025 Chromatin binding of SMCHD1 genome-wide including on the Xi is critically dependent on LRIF1 mediating interaction with H3K9me2/3-modified nucleosomes. ATP hydrolysis by the GHKL ATPase domain is required for selective enrichment of SMCHD1 at specific chromatin regions and for gene silencing on the Xi. A BAMS gain-of-function mutation (G137E) accelerates Xi recruitment and increases Xi compaction. Live-cell and single-molecule imaging, engineered ATPase domain mutations, LRIF1 depletion, H3K9me2/3 interaction assay, Xi silencing readout bioRxivpreprint Medium
2025 Full-length SMCHD1 homodimer directly bridges and compacts DNA in an ATP-independent manner, forming large protein-DNA clusters. The linker domain confers conformational flexibility (compact vs. extended). Both the ATPase and hinge domains are required for DNA compaction; the coiled-coil domain facilitates LRIF1 interaction. Addition of ATP paradoxically reduces compaction rate. Biophysical DNA compaction assay with reconstituted protein, nucleosome array clustering assay, domain deletion analysis, SMCHD1-LRIF1 interaction assay bioRxivpreprint Medium

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nature genetics 502 23143600
2008 SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nature genetics 285 18425126
2012 Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Developmental cell 155 22841499
2013 Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway. Nature structural & molecular biology 154 23542155
2013 The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. American journal of human genetics 148 24075187
2014 Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Human molecular genetics 142 25256356
2018 SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X. Cell 134 29887375
2017 SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nature genetics 117 28067909
2017 De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nature genetics 96 28067911
2014 Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. European journal of human genetics : EJHG 90 25370034
2013 Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Molecular and cellular biology 89 23754746
2019 The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome. Nature communications 87 30604745
2015 Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. Proceedings of the National Academy of Sciences of the United States of America 85 26091879
2018 Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters. Nature structural & molecular biology 77 30127357
2013 Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenetics & chromatin 76 23819640
2013 A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology 74 23284062
2019 FSHD1 and FSHD2 form a disease continuum. Neurology 69 30979860
2019 PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments. Nature communications 68 31270318
2016 Allele-specific DNA hypomethylation characterises FSHD1 and FSHD2. Journal of medical genetics 61 26831754
2015 Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome. Molecular and cellular biology 61 26391951
2018 Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway. Cell reports 59 30428357
2015 Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 58 26575099
2019 SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite. Nucleic acids research 46 30698748
2021 The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins. Science advances 41 33523915
2020 Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei. PLoS genetics 39 32365093
2011 Expression profiling of FSHD-1 and FSHD-2 cells during myogenic differentiation evidences common and distinctive gene dysregulation patterns. PloS one 39 21695143
2012 Epigenetic regulator Smchd1 functions as a tumor suppressor. Cancer research 37 23269277
2015 Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome. Human mutation 34 25820463
2017 SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skeletal muscle 32 28587678
2018 FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. The Journal of biological chemistry 31 29748383
2013 Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2. Neuromuscular disorders : NMD 31 24128691
2019 Intronic SMCHD1 variants in FSHD: testing the potential for CRISPR-Cas9 genome editing. Journal of medical genetics 30 31676591
2019 SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain. Journal of medical genetics 29 31243061
2017 Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2. European journal of human genetics : EJHG 28 29162933
2022 Xist-mediated silencing requires additive functions of SPEN and Polycomb together with differentiation-dependent recruitment of SmcHD1. Cell reports 27 35584662
2018 Role of SmcHD1 in establishment of epigenetic states required for the maintenance of the X-inactivated state in mice. Development (Cambridge, England) 27 30126901
2019 SMCHD1 terminates the first embryonic genome activation event in mouse two-cell embryos and contributes to a transcriptionally repressive state. American journal of physiology. Cell physiology 26 31365290
2020 Smchd1 is a maternal effect gene required for genomic imprinting. eLife 25 33186096
2012 Diagnosis by sequencing: correction of misdiagnosis from FSHD2 to LGMD2A by whole-exome analysis. European journal of human genetics : EJHG 23 22378277
2015 Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. European journal of human genetics : EJHG 22 25782668
2014 Epigenetic characterization of the growth hormone gene identifies SmcHD1 as a regulator of autosomal gene clusters. PloS one 22 24818964
2016 The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain. The Biochemical journal 21 27059856
2021 Precise Epigenetic Analysis Using Targeted Bisulfite Genomic Sequencing Distinguishes FSHD1, FSHD2, and Healthy Subjects. Diagnostics (Basel, Switzerland) 20 34441403
2018 Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model. Human molecular genetics 20 29281018
2022 SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice. Development (Cambridge, England) 18 35831949
2014 Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy. European journal of human genetics : EJHG 18 24755953
2014 SMCHD1 accumulates at DNA damage sites and facilitates the repair of DNA double-strand breaks. Journal of cell science 18 24790221
2020 SMCHD1 promotes ATM-dependent DNA damage signaling and repair of uncapped telomeres. The EMBO journal 17 32080884
2019 The variability of SMCHD1 gene in FSHD patients: evidence of new mutations. Human molecular genetics 17 31600781
2018 Novel key roles for structural maintenance of chromosome flexible domain containing 1 (Smchd1) during preimplantation mouse development. Molecular reproduction and development 17 29900695
2016 The hinge domain of the epigenetic repressor Smchd1 adopts an unconventional homodimeric configuration. The Biochemical journal 17 26733688
2016 Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations. Neuromuscular disorders : NMD 16 27061275
2023 SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease. Nature communications 14 37749075
2020 Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency. Scientific reports 14 32620854
2020 Relating SMCHD1 structure to its function in epigenetic silencing. Biochemical Society transactions 14 32779700
2017 Many faces of SMCHD1. Nature genetics 14 28138148
2018 Digenic Inheritance of Shortened Repeat Units of the D4Z4 Region and a Loss-of-Function Variant in SMCHD1 in a Family With FSHD. Frontiers in neurology 13 30546343
2016 Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report. BMC medical genetics 12 27634379
2014 Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) promotes non-homologous end joining and inhibits homologous recombination repair upon DNA damage. The Journal of biological chemistry 12 25294876
2023 Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses. mBio 11 37010434
2019 A New Role for SMCHD1 in Life's Master Switch and Beyond. Trends in genetics : TIG 11 31668908
2022 Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants. Neurology 10 35121673
2022 HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring. Nature communications 10 35739109
2019 A ubiquitin-like domain is required for stabilizing the N-terminal ATPase module of human SMCHD1. Communications biology 10 31312724
2011 Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo. Chromosoma 10 21553025
2023 SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action. Communications biology 9 37380887
2015 Transcriptional profiling of the epigenetic regulator Smchd1. Genomics data 9 26981392
2024 DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis. Science advances 7 38809976
2023 In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype. Nucleic acids research 7 37334829
2024 SMCHD1 activates the expression of genes required for the expansion of human myoblasts. Nucleic acids research 5 38994563
2022 Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation. Epigenetics & chromatin 5 35843975
2025 SMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts. Nature communications 4 40715155
2023 Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant. The Journal of craniofacial surgery 4 36944600
2021 A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression. Scientific reports 4 34880314
2018 Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures. Human molecular genetics 4 29741619
2018 Identification of SMCHD1 domains for nuclear localization, homo-dimerization, and protein cleavage. Skeletal muscle 4 30071896
2024 Hemiarhinia caused by a missense variation in SMCHD1: A mild phenotype in the clinical spectrum of Bosma arhinia microphthalmia syndrome. American journal of medical genetics. Part A 3 38808953
2024 Genome-wide CRISPR screenings identified SMCHD1 as a host-restricting factor for AAV transduction. PLoS pathogens 3 38976714
2024 SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance. European journal of human genetics : EJHG 3 39725690
2021 SMCHD1's ubiquitin-like domain is required for N-terminal dimerization and chromatin localization. The Biochemical journal 3 34109974
2020 The effects of the DNA Demethylating reagent, 5-azacytidine on SMCHD1 genomic localization. BMC genetics 3 31941450
2019 Role of the Chromosome Architectural Factor SMCHD1 in X-Chromosome Inactivation, Gene Regulation, and Disease in Humans. Genetics 3 31420322
2022 Epigenetic modifier SMCHD1 maintains a normal pool of long-term hematopoietic stem cells. iScience 2 35856023
2020 Generation of a transgene-free iPSC line and genetically modified line from a facioscapulohumeral muscular dystrophy type 2 (FSHD2) patient with SMCHD1 p.Lys607Ter mutation. Stem cell research 2 32711388
2025 Metabolic-immune crosstalk in myocardial infarction: RLF and SMCHD1 identified as causal therapeutic targets via integrated lactylation-MR analysis. Frontiers in cell and developmental biology 1 41158309
2024 Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report. Endocrinologia, diabetes y nutricion 1 38555111
2024 Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report. BMC medical genomics 1 38773541
2023 Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism. Heliyon 1 38148819
2018 Different clinicopathological features between Japanese siblings with facioscapulohumeral muscular dystrophy 2 with a novel nonsense SMCHD1 mutation (Arg552∗). Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 1 30327220
2026 SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells. bioRxiv : the preprint server for biology 0 41756954
2024 SMCHD1 maintains heterochromatin and genome compartments in human myoblasts. bioRxiv : the preprint server for biology 0 39026812
2015 Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD. Human genomics 0 26446085

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