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SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells

ABSTRACT: Human SMCHD1 is a chromatin architectural regulator linked to facioscapulohumeral muscular dystrophy (FSHD), but how SMCHD1 regulates myogenic transcription independently of DUX4 remains unclear. Here, we show that SMCHD1 safeguards enhancer organization and three-dimensional (3D) genome architecture in human myoblasts. Loss of SMCHD1 leads to widespread gains in chromatin accessibility, aberrant transcriptional changes, and a global redistribution of the myogenic transcription factor MYOD1. Integrative analyses of histone modifications, chromatin accessibility, Hi-C looping, and Activity-by-Contact enhancer–gene modeling reveal that SMCHD1 deletion rewires the landscape of clustered enhancers and promotes the emergence of a MYOD1-related network of enhancer elements, termed MYOD1 enhancer Nexuses. These structures are marked by increased enhancer–enhancer connectivity, increased local 3D chromatin interactions, and coordinated activation of myogenic and FSHD-associated genes. Together, our findings identify SMCHD1 as a key architectural constraint that suppresses hyperactive enhancer networks, thereby preserving transcriptional homeostasis in myoblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319462 | GEO | 2026/09/11

REPOSITORIES: GEO

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SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells [RNA-Seq]

Project description:Human SMCHD1 is a chromatin architectural regulator linked to facioscapulohumeral muscular dystrophy (FSHD), but how SMCHD1 regulates myogenic transcription independently of DUX4 remains unclear. Here, we show that SMCHD1 safeguards enhancer organization and three-dimensional (3D) genome architecture in human myoblasts. Loss of SMCHD1 leads to widespread gains in chromatin accessibility, aberrant transcriptional changes, and a global redistribution of the myogenic transcription factor MYOD1. Integrative analyses of histone modifications, chromatin accessibility, Hi-C looping, and Activity-by-Contact enhancer–gene modeling reveal that SMCHD1 deletion rewires the landscape of clustered enhancers and promotes the emergence of a MYOD1-related network of enhancer elements, termed MYOD1 enhancer Nexuses. These structures are marked by increased enhancer–enhancer connectivity, increased local 3D chromatin interactions, and coordinated activation of myogenic and FSHD-associated genes. Together, our findings identify SMCHD1 as a key architectural constraint that suppresses hyperactive enhancer networks, thereby preserving transcriptional homeostasis in myoblasts.

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SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells [ChIP-seq]

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SMCHD1 activates the expression of genes required for the expansion of human myoblasts (RNA-seq)

Project description:In human muscle, SMCHD1 mutations are associated with the onset of FSHD2, but the mechanism driving the disease onset remains unclear. A commonly accepted explanation is the loss of SMCHD1 binding to the D4Z4 locus activates the expression of DUX4 in FSHD2 muscle. In this study, we used human myoblasts having DUX4 non-permissive 4qB alleles as a model to study DUX4-independent functions of SMCHD1 on myoblast cell growth. Surprisingly, depletion of SMCHD1 in these cells resulted in a cell proliferation defect. Despite the absence of DUX4 target genes’ activation, these cells showed a repression of PAX7 target genes (a hallmark of FSHD) and similar changes in expression profile compared to FSHD myoblasts. Interestingly, downregulation of cell proliferation-related genes and dysregulation of fibroblasts-specific genes were observed in SMCHD1 knockdown myoblasts and FSHD2 myoblasts but not FSHD1 myoblasts. Additionally, we identified LAP2 as direct targets of SMCHD1. Depletion of LAP2 leads to cell proliferation defect similar to the effect after SMCHD1 knockdown. These data imply that DUX4 is not the only driver for the onset of FSHD, and SMCHD1 has DUX4-independent functions in muscle growth and development.

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SMCHD1 activates the expression of genes required for the expansion of human myoblasts (ChIP-seq)

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Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is caused by insufficient epigenetic repression of D4Z4 macrosatellite repeat where DUX4, an FSHD causing gene is embedded. There are two forms of FSHD, FSHD1 with contraction of D4Z4 repeat and FSHD2 with chromatin compaction defects mostly due to SMCHD1 mutation. Previous reports showed DUX4-induced gene expression changes as well as changes in microRNA expression in FSHD muscle cells. However, a genome wide analysis of small noncoding RNAs that might be regulated by DUX4 or by mutations in SMCHD1 has not been reported yet. Here, we identified several types of small noncoding RNAs including known microRNAs that are differentially expressed in FSHD2 muscle cells compared to control. Although fewer small RNAs were differentially expressed during muscle differentiation in FSHD2 cells compared to controls, most of the known myogenic microRNAs, such as miR1, miR133a, and miR206 were induced in both FSHD2 and control muscle cells during differentiation. Our small RNA sequencing data analysis also revealed both DUX4- and SMCHD1-specific changes in FSHD2 muscle cells. Six FSHD2 microRNAs were affected by DUX4 overexpression in control myoblasts, whereas increased expression of tRNAs and 5S rRNAs in FSHD2 muscle cells was largely recapitulated in SMCHD1-depleted control myoblasts. Altogether, our studies suggest that the small noncoding RNA transcriptome changes in FSHD2 might be different from those in FSHD1 and that these differences may provide new diagnostic and therapeutic tools specific to FSHD2.

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Modulating MyoD1 dosage activates alternate cell fate beyond myogenic differentiation [ATAC-seq]

Project description:The study investigates how MyoD1 dosage controls myogenic cell fate, employing bulk RNA-seq, ATAC-seq, and CUT&RUN. We determined genome-wide transcriptional, chromatin accessibility, and MyoD1 binding profiles in C2C12 myoblasts expressing endogenous Halo-tagged MyoD1 or doxycycline-inducible Halo–MyoD1, under growth and differentiation conditions with low or high MyoD1 dosage.

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SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells

Project description:SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells

| PRJNA1423322 | ENA

Genome-wide identification of enhancers in skeletal muscle

Project description:In an effort to identify the compendium of regulatory elements that govern myogenic differentiation, we generated chromatin state maps based on the recruitment of factors (p300 and PolII) and histone modifications (H3K4me1, H3K27ac) that typify enhancers in myoblasts and myotubes. We found a remarkable concordance between the location of these newly defined, active enhancers and MyoD1 binding events. In addition, we found a striking association between the position of enhancers and RNA polymerase II recruitment, which resulted in the expression of previously disclosed non-coding RNAs, as well as potentially new transcripts identified ab initio, throughout the enhancer region. Mapping of H3K27ac and p300 in growing myoblasts (MB) and fully differentiated myotubes (MT). Mapping of c-Jun in growing myoblasts (MB).

2012-12-15 | E-GEOD-37525 | biostudies-arrayexpress

A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.

Project description:Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor, which is mutated in >95% of Facioscapulohumeral dystrophy (FSHD) type 2 cases. In FSHD2, SMCHD1 mutations ultimately result in the presence of the cleavage stage transcription factor DUX4 in muscle cells due to a failure in epigenetic repression of the D4Z4 macrosatellite repeat on chromosome 4q, which contains the DUX4 locus. While binding of SMCHD1 to D4Z4 and its necessity to maintain a repressive D4Z4 chromatin structure are well documented, it is unclear how SMCHD1 is recruited to D4Z4, and how it exerts its repressive properties on the chromatin. Here, we employ a quantitative proteomics approach to identify and characterize novel SMCHD1 interacting proteins, and assess their functionality in D4Z4 repression. We identify 47 robust SMCHD1 interactors, of which 19 are present in D4Z4 chromatin. We demonstrate that one of these SMCHD1 interacting proteins in D4Z4, RuvB-like 1 (RUVBL1) is indeed required for maintaining DUX4 silencing in FSHD myocytes. We also confirm the interaction of SMCHD1 with EZH inhibitory protein (EZHIP), which prevents global H3K27me3 deposition by the Polycomb repressive complex PRC2, providing novel insights into the potential function of SMCHD1 in the repression of DUX4 in the early stages of embryogenesis. The SMCHD1 interactome outlined herein can thus provide further direction into research on the potential function of SMCHD1 at genomic loci where SMCHD1 is known to act, such as D4Z4 repeats, the inactive X chromosome, autosomal gene clusters, imprinted loci and telomeres.

2021-12-15 | PXD023993 | Pride

Expression profiling of 4q-linked and phenotypic FSHD in different steps of myogenic differentiation

Project description:The specific gene(s) responsible for FSHD phenotype have not yet been identified. We used the Human GeneChip Exon 1.0 ST platform to analyze the global gene expression profiles of FSHD-1, FSHD-2 and controls during myogenic differentiation. In this dataset, we include the expression data of human primary myoblasts obtained from three FSHD-1 and two FSHD-2 patients, and three healthy controls (CN). This data are used to evaluate the molecular perturbation of FSHD upon muscle differentiation; we compared patients and CN proliferating myoblasts as well as the corresponding myotubes obtained after 8 days of cell differentiation. 16 expression profiles were generated from 6 different cell types: including myoblasts and myotubes from healthy donors and FSHD-1 and FSHD-2 patients. Gene probesets with P < 0.01 and FC > 2 were selected in FSHD-1 assay, whereas P < 0.001 and FC > 2 were used in FSHD-2, in the attempt to overcame problems due to the small sample size analyzed.

2011-07-07 | E-GEOD-26061 | biostudies-arrayexpress

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