Trends in Genetics
Volume 33, Issue 4, April 2017, Pages 233-243
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Review
The Epigenetic Regulator SMCHD1 in Development and Disease

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The transcriptional repressor SMCHD1 hydrolyses ATP through its N-terminal GHKL ATPase domain and directly binds to oligonucleotides through its C-terminal hinge domain.

Loss-of-function mutations throughout SMCHD1 underlie the late-onset, progressive muscular dystrophy FSHD2 and modify disease severity in FSHD1 patients.

Missense mutations within, or proximal to, the SMCHD1 ATPase domain have been found in Bosma arhinia micropthalmia syndrome patients.

Whether mutations in BAMS enhance or suppress SMCHD1 function remains a matter of controversy.

SMCHD1 occupies distinct loci genome-wide, and loss of Smchd1 results in altered chromatin modifications, most markedly DNA hypomethylation, and changes in gene expression.

SMCHD1 shares binding sites with CTCF, and, at one characterised locus, the clustered protocadherins, SMCHD1, and CTCF mediate opposing effects on gene expression.

It has very recently become clear that the epigenetic modifier SMCHD1 has a role in two distinct disorders: facioscapulohumoral muscular dystrophy (FSHD) and Bosma arhinia and micropthalmia (BAMS). In the former there are heterozygous loss-of-function mutations, while both gain- and loss-of-function mutations have been proposed to underlie the latter. These findings have led to much interest in SMCHD1 and how it works at the molecular level. We summarise here current understanding of the mechanism of action of SMCHD1, its role in these diseases, and what has been learnt from study of mouse models null for Smchd1 in the decade since the discovery of SMCHD1.

Section snippets

FSHD

FSHD is a late-onset, progressive, muscular dystrophy which first presents in the muscles of the upper extremities and follows a descending progression. In severe cases FSHD can leave patients wheelchair-bound (reviewed in [6]). FSHD is the third most common neuromuscular condition and has been estimated to affect up to 1 in 8000 people worldwide [7]. Although landmark findings have advanced our understanding of the genetic and molecular basis for FSHD in the past decade, treatment for FSHD

BAMS

BAMS is the congenital absence of the nose and a reduction in eye size, often accompanied by a series of other malformations 17, 18. BAMS was formally described by Bosma in 1981 who observed the above symptoms in two unrelated boys with healthy parents [18]. A rare condition, it has since been reported in only 50 patients worldwide. Arhinia poses problems for affected individuals from birth, and extensive surgery is often required for BAMS patients from a young age to prevent structural

SMCHD1 As a Transcriptional Repressor

Much in the same way as human SMCHD1 functions at the D4Z4 array, SMCHD1 was first implicated in epigenetic control through its role in repeat-induced silencing of a murine multicopy GFP transgene for which expression is also variegated (Figure 2B) [24]. This strain was used in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to find novel epigenetic modifiers. The modifier of murine metastable epialleles dominant 1 (MommeD1) line generated in this screen harbours a nonsense mutation in Smchd1

SMCHD1 Is Crucial for XCI

In the absence of SMCHD1, both random XCI in the embryo and imprinted XCI in the placenta fail [22]. In the embryo, the early stages of XCI proceed normally, indicated by the accumulation of Xist long non-coding RNA (lncRNA) and H3K27me3 on the inactive X chromosome (Xi). However, there is a failure to properly establish or maintain silencing on the Xi, as indicated by the developmental window during which Smchd1MommeD1/MommeD1 female embryos die [22]. This observation is supported by in vitro

SMCHD1 Regulates Autosomal Monoallelic Gene Expression

Despite the prominent role of SMCHD1 in XCI, and the viability of Smchd1 null male mice on some genetic backgrounds, the ubiquitous expression of SMCHD1 in male and female cells suggests a broader role for SMCHD1 in regulating transcription 22, 24. Global expression analyses of cells and embryos derived from male Smchd1MommeD1/MommeD1 mice have shown that, in the absence of SMCHD1, autosomal monoallelic gene expression is perturbed at some imprinted clusters and at the clustered protocadherin

Molecular Mechanisms

Recent advances in our understanding of SMCHD1 structure and function, coupled with loss-of-function studies, have provided the first glimpses into the mechanisms underpinning SMCHD1 molecular function. Such an understanding would facilitate the development of therapeutic strategies to counter FSHD.

SMCHD1 is a non-canonical member of the SMC protein family, possessing a C-terminal SMC hinge domain and an N-terminal ATPase domain 4, 5. SMC proteins heterodimerise to form specific complexes

Model

SMCHD1 functions at loci that are subject to stable and heritable silencing, and these employ multiple epigenetic mechanisms to ensure silencing is maintained. When SMCHD1 is lost from these loci, there are widespread changes to the local chromatin environment, most markedly a dramatic loss of DNA methylation. At many SMCHD1 target enhancers and promoters, SMCHD1 and CTCF appear to have opposing roles. Indeed, while CTCF preferentially binds to unmethylated sequences, SMCHD1 has a preference

Concluding Remarks and Future Perspectives

SMCHD1 is an interesting case in that mutations that alter SMCHD1 function drive divergent human diseases that are characterised by distinct disease onset and affected tissues. While BAMS is a congenital disorder where treatment to inhibit SMCHD1 would not be of therapeutic benefit, FSHD can be diagnosed at the early stages of disease progression. The discovery of mutations that enhance the ATPase activity of SMCHD1 in BAMS patients raises the possibility that SMCHD1 has the potential to be

Acknowledgments

N.J. was supported by an Australian Postgraduate Award from the University of Melbourne. K.C. was supported by a Cancer Council Victoria Postdoctoral Fellowship. J.M.M. and M.E.B. were supported by National Health and Medical Research Council of Australia (NHMRC) R.D. Wright Fellowships (APP1105754 and APP1110206 respectively). The studies from laboratories of the authors reviewed herein were enabled by NHMRC Project grants 1045936 and 1098290, with additional support from NHMRC IRIISS 9000220

Glossary

Chromatin relaxation
the loss of heterochromatic chromatin modifications, such as DNA methylation, and histone H3 lysine 9 trimethylation (H3K9me3), and the simultaneous accumulation of euchromatic chromatin modifications, such as H3K4me3, which is often accompanied by transcriptional upregulation.
DNA hypomethylation
the loss of the methyl group from 5-methylcytosines.
Enhancers
regulatory sequences of DNA that can be bound by transcription factors and epigenetic modifiers and enhance the

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      In FSHD, heterozygous loss-of-function mutation of SMCHD1 results in relaxation of repressive chromatin structures at the D4Z4 macrosatellite repeat, leading to aberrant, variegated expression of the myotoxic gene DUX4 in skeletal muscle (Jansz et al., 2017; Lemmers et al., 2012). In BAMS, pathogenic SMCHD1 missense mutations fall exclusively within its extended ATPase domain; however, reports differ as to whether these variants lead to a loss or gain of SMCHD1 function (Gordon et al., 2017; Gurzau et al., 2018; Jansz et al., 2017; Lemmers et al., 2019; Shaw et al., 2017). Mechanistically, SMCHD1 works by maintaining long-range repressive chromatin structures; in the case of the inactive X chromosome (Xi), ablation of SMCHD1 leads to a strengthening of short-range interactions, altering the Xi architecture such that it adopts a structure more reminiscent of its active counterpart (Gdula et al., 2019; Jansz et al., 2018; Wang et al., 2018).

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      Dux and Zscan4 mRNAs peak in expression at the early two-cell stage and are rapidly downregulated between 3 and 9 h after cleavage (Figure 1) [1]. ZSCAN4 nuclear protein staining also declines by 9 h post-cleavage (Figure 1) [1], indicating that the temporal regulation of SMCHD1 is consistent with a possible role in repressing DUX expression and EGA1 in two-cell embryos; also consistent with this, SMCHD1 represses DUX in somatic tissues [3]. The contribution of SMCHD1 in controlling EGA1 was tested in small interfering (si)RNA knockdown studies using siRNA microinjection at the one-cell stage [1].

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