ArticleSkeletal muscle2017
SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes.
Article in Skeletal muscle, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- Cranial placode differentiation defect in individuals born without a nose.Stem cell reports · 2026Article
- Identification of SENP7 and UTF1/VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study.Molecular psychiatry · 2026Article
- Clinical and molecular characterization of 18p deletion syndrome and a novel case with reproductive disorder.Molecular cytogenetics · 2026Article
- A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing.Human molecular genetics · 2025Article
- DUX4 activates common and context-specific intergenic transcripts and isoforms.Science advances · 2025Article
- SMCHD1 activates the expression of genes required for the expansion of human myoblasts.Nucleic acids research · 2024Article
- Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.Nature communications · 2024Article
- Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing.Genome research · 2023Article
- In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype.Nucleic acids research · 2023Article
- SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.Communications biology · 2023Article
- Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing.bioRxiv : the preprint server for biology · 2023Article
- Facioscapulohumeral muscular dystrophy: the road to targeted therapies.Nature reviews. Neurology · 2023Review
- Epigenetic modifier SMCHD1 maintains a normal pool of long-term hematopoietic stem cells.iScience · 2022Article
- A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.Scientific reports · 2021Article
- Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7.EMBO molecular medicine · 2021Review
- Relating SMCHD1 structure to its function in epigenetic silencing.Biochemical Society transactions · 2020Review
- The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.Human molecular genetics · 2019Article
- Role of the Chromosome Architectural Factor SMCHD1 in X-Chromosome Inactivation, Gene Regulation, and Disease in Humans.Genetics · 2019Article
- 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 · 2019Article
- SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite.Nucleic acids research · 2019Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundFacioscapulohumeral muscular dystrophy (FSHD) is in most cases caused by a contraction of the D4Z4 macrosatellite repeat on chromosome 4 (FSHD1) or by mutations in the SMCHD1 or DNMT3B gene (FSHD2). Both situations result in the incomplete epigenetic repression of the D4Z4-encoded retrogene DUX4 in somatic cells, leading to the aberrant expression of DUX4 in the skeletal muscle. In mice, Smchd1 regulates chromatin repression at different loci, having a role in CpG methylation establishment and/or maintenance.
methodsTo investigate the global effects of harboring heterozygous SMCHD1 mutations on DNA methylation in humans, we combined 450k methylation analysis on mononuclear monocytes from female heterozygous SMCHD1 mutation carriers and unaffected controls with reduced representation bisulfite sequencing (RRBS) on FSHD2 and control myoblast cell lines. Candidate loci were then evaluated for SMCHD1 binding using ChIP-qPCR and expression was evaluated using RT-qPCR.
resultsWe identified a limited number of clustered autosomal loci with CpG hypomethylation in SMCHD1 mutation carriers: the protocadherin (PCDH) cluster on chromosome 5, the transfer RNA (tRNA) and 5S rRNA clusters on chromosome 1, the HOXB and HOXD clusters on chromosomes 17 and 2, respectively, and the D4Z4 repeats on chromosomes 4 and 10. Furthermore, minor increases in RNA expression were seen in FSHD2 myoblasts for some of the PCDHβ cluster isoforms, tRNA isoforms, and a HOXB isoform in comparison to controls, in addition to the previously reported effects on DUX4 expression. SMCHD1 was bound at DNAseI hypersensitivity sites known to regulate the PCDHβ cluster and at the chromosome 1 tRNA cluster, with decreased binding in SMCHD1 mutation carriers at the PCDHβ cluster sites.
conclusionsOur study is the first to investigate the global methylation effects in humans resulting from heterozygous mutations in SMCHD1. Our results suggest that SMCHD1 acts as a repressor on a limited set of autosomal gene clusters, as an observed reduction in methylation associates with a loss of SMCHD1 binding and increased expression for some of the loci.
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