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Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE112097 | GEO | 2018/08/28

REPOSITORIES: GEO

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Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [RNA-seq]

Project description:It has been shown that functional deficiency of SmcHD1, a noncanonical member of SMC family proteins, results in derepression of X-inactivated genes in postimplantation female mouse embryos. In this study, we found that derepression of X-inactivated genes accompanied a local reduction in the enrichment of H3K27me3 in mouse embryonic fibroblasts (MEFs) prepared from female fetuses deficient for SmcHD1.

2018-08-28 | GSE112095 | GEO

Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [ChIP-seq]

2018-08-28 | GSE112096 | GEO

Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation

Project description:Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation

| PRJNA439282 | ENA

Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [RNA-seq]

Project description:Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [RNA-seq]

| PRJNA439360 | ENA

Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [ChIP-seq]

Project description:Role of SmcHD1 in the establishment of the epigenetic states required for the maintenance of X chromosome inactivation [ChIP-seq]

| PRJNA439361 | ENA

Role of the Chromosome Architectural Factor SMCHD1 in X-Chromosome Inactivation, Gene Regulation, and Disease in Humans.

Project description:Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is an architectural factor critical for X-chromosome inactivation (XCI) and the repression of select autosomal gene clusters. In mice, homozygous nonsense mutations in Smchd1 cause female-specific embryonic lethality due to an XCI defect. However, although human mutations in SMCHD1 are associated with congenital arhinia and facioscapulohumeral muscular dystrophy type 2 (FSHD2), the diseases do not show a sex-specific bias, despite the essential nature of XCI in humans. To investigate whether there is a dosage imbalance for the sex chromosomes, we here analyze transcriptomic data from arhinia and FSHD2 patient blood and muscle cells. We find that X-linked dosage compensation is maintained in these patients. In mice, SMCHD1 controls not only protocadherin (Pcdh) gene clusters, but also Hox genes critical for craniofacial development. Ablating Smchd1 results in aberrant expression of these genes, coinciding with altered chromatin states and three-dimensional (3D) topological organization. In a subset of FSHD2 and arhinia patients, we also found dysregulation of clustered PCDH, but not HOX genes. Overall, our study demonstrates preservation of XCI in arhinia and FSHD2, and implicates SMCHD1 in the regulation of the 3D organization of select autosomal gene clusters.

| S-EPMC6781896 | biostudies-literature

Investigating the role of SMCHD1 in de novo X chromosome inactivation

Project description:To investigate the effect of Smchd1 ablation on de novo X chromosome inactivation (XCI), we derived clonal neural progenitor cells (NPCs) from Smchd1+/+ (wild-type, WT) and Smchd1-/- mouse embryonic stem cells (ES cells; ESC). We generated allele-specific RNA-seq datasets from WT and Smchd1-/- NPCs to examine the effect of Smchd1 ablation on gene silencing. In addition, we produced allele-specific ChIP-seq profiles of H3K4me3, H3K27me3, CTCF, and RAD21 and Xist CHART-seq profiles in WT and Smchd1-/- NPCs to investigate the role of SMCHD1 on the distribution of euchromatin, facultative heterochromatin, architectural proteins, and Xist RNA on the inactive X chromosome (Xi). To determine the localization of SMCHD1 on the Xi, we employed allele-specific DamID-seq to map SMCHD1-binding regions in female mouse embryonic fibroblasts. Furthermore, we performed in situ Hi-C on WT NPCs, Smchd1-/- NPCs, and female ES cells undergoing XCI, in order to explore the role of SMCHD1 in regulating the higher-order structure of the Xi.

2018-06-07 | GSE99991 | GEO

Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica.

Project description:Evidence from a few genes in diverse species suggests that X-chromosome inactivation (XCI) in marsupials is characterized by exclusive, but leaky inactivation of the paternally derived X chromosome. To study the phenomenon of marsupial XCI more comprehensively, we profiled parent-of-origin allele-specific expression, DNA methylation, and histone modifications in fetal brain and extra-embryonic membranes in the gray, short-tailed opossum (Monodelphis domestica). The majority of X-linked genes (152 of 176 genes with trackable SNP variants) exhibited paternally imprinted expression, with nearly 100% of transcripts derived from the maternal allele; whereas 24 loci (14%) escaped inactivation, showing varying levels of biallelic expression. In addition to recently reported evidence of marsupial XCI regulation by the noncoding Rsx transcript, strong depletion of H3K27me3 at escaper gene loci in the present study suggests that histone state modifications also correlate strongly with opossum XCI. In contrast to mouse, the opossum did not show an association between X-linked gene expression and promoter DNA methylation, with one notable exception. Unlike all other X-linked genes examined, Rsx was differentially methylated on the maternal and paternal X chromosomes, and expression was exclusively from the inactive (paternal) X chromosome. Our study provides the first comprehensive catalog of parent-of-origin expression status for X-linked genes in a marsupial and sheds light on the regulation and evolution of imprinted XCI in mammals.

| S-EPMC3875863 | biostudies-other

Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes.

Project description:The Smchd1 gene encodes a large protein with homology to the SMC family of proteins involved in chromosome condensation and cohesion. Previous studies have found that Smchd1 has an important role in CpG island (CGI) methylation on the inactive X chromosome (Xi) and in stable silencing of some Xi genes. In this study, using genome-wide expression analysis, we showed that Smchd1 is required for the silencing of around 10% of the genes on Xi, apparently independent of CGI hypomethylation, and, moreover, that these genes nonrandomly occur in clusters. Additionally, we found that Smchd1 is required for CpG island methylation and silencing at a cluster of four imprinted genes in the Prader-Willi syndrome (PWS) locus on chromosome 7 and genes from the protocadherin-alpha and -beta clusters. All of the affected autosomal loci display developmentally regulated brain-specific methylation patterns which are lost in Smchd1 homozygous mutants. We discuss the implications of these findings for understanding the function of Smchd1 in epigenetic regulation of gene expression.

| S-EPMC3753908 | biostudies-literature

H3K9me3 maintenance on a human artificial chromosome is required for segregation but not centromere epigenetic memory.

Project description:Most eukaryotic centromeres are located within heterochromatic regions. Paradoxically, heterochromatin can also antagonize de novo centromere formation, and some centromeres lack it altogether. In order to investigate the importance of heterochromatin at centromeres, we used epigenetic engineering of a synthetic alphoidtetO human artificial chromosome (HAC), to which chimeric proteins can be targeted. By tethering the JMJD2D demethylase (also known as KDM4D), we removed heterochromatin mark H3K9me3 (histone 3 lysine 9 trimethylation) specifically from the HAC centromere. This caused no short-term defects, but long-term tethering reduced HAC centromere protein levels and triggered HAC mis-segregation. However, centromeric CENP-A was maintained at a reduced level. Furthermore, HAC centromere function was compatible with an alternative low-H3K9me3, high-H3K27me3 chromatin signature, as long as residual levels of H3K9me3 remained. When JMJD2D was released from the HAC, H3K9me3 levels recovered over several days back to initial levels along with CENP-A and CENP-C centromere levels, and mitotic segregation fidelity. Our results suggest that a minimal level of heterochromatin is required to stabilize mitotic centromere function but not for maintaining centromere epigenetic memory, and that a homeostatic pathway maintains heterochromatin at centromeres.This article has an associated First Person interview with the first authors of the paper.

| S-EPMC7390644 | biostudies-literature

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