Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation

Arne Mould, Zhenyi Pang, Miha Pakusch, Ian Tonks, Mitchell Stark, Dianne Carrie, Pamela Mukhopadhyay, Annica Seidel, Jonathan Ellis, Janine Deakin, Matthew Wakefield, Lutz Krause, Marnie Blewitt, Graham Kay

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Abstract

Background: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. Results: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdha, Pcdhß, and Pcdh?) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. Conclusions: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases.
Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalEpigenetics and Chromatin
Volume6:19
DOIs
Publication statusPublished - 2013
Externally publishedYes

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X Chromosome Inactivation
Multigene Family
Genes
Epigenomics
Facioscapulohumeral Muscular Dystrophy
Essential Genes
Muscle Weakness
Placenta
Methylation
Single Nucleotide Polymorphism
Embryonic Structures
Genome
RNA
Mutation

Cite this

Mould, Arne ; Pang, Zhenyi ; Pakusch, Miha ; Tonks, Ian ; Stark, Mitchell ; Carrie, Dianne ; Mukhopadhyay, Pamela ; Seidel, Annica ; Ellis, Jonathan ; Deakin, Janine ; Wakefield, Matthew ; Krause, Lutz ; Blewitt, Marnie ; Kay, Graham. / Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. In: Epigenetics and Chromatin. 2013 ; Vol. 6:19. pp. 1-16.
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title = "Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation",
abstract = "Background: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. Results: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdha, Pcdh{\ss}, and Pcdh?) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. Conclusions: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases.",
keywords = "Clustered protocadherins, Genomic imprinting, Monoallelic expression, Smchd1, X inactivation.",
author = "Arne Mould and Zhenyi Pang and Miha Pakusch and Ian Tonks and Mitchell Stark and Dianne Carrie and Pamela Mukhopadhyay and Annica Seidel and Jonathan Ellis and Janine Deakin and Matthew Wakefield and Lutz Krause and Marnie Blewitt and Graham Kay",
year = "2013",
doi = "10.1186/1756-8935-6-19",
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Mould, A, Pang, Z, Pakusch, M, Tonks, I, Stark, M, Carrie, D, Mukhopadhyay, P, Seidel, A, Ellis, J, Deakin, J, Wakefield, M, Krause, L, Blewitt, M & Kay, G 2013, 'Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation', Epigenetics and Chromatin, vol. 6:19, pp. 1-16. https://doi.org/10.1186/1756-8935-6-19

Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. / Mould, Arne; Pang, Zhenyi; Pakusch, Miha; Tonks, Ian; Stark, Mitchell; Carrie, Dianne; Mukhopadhyay, Pamela; Seidel, Annica; Ellis, Jonathan; Deakin, Janine; Wakefield, Matthew; Krause, Lutz; Blewitt, Marnie; Kay, Graham.

In: Epigenetics and Chromatin, Vol. 6:19, 2013, p. 1-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation

AU - Mould, Arne

AU - Pang, Zhenyi

AU - Pakusch, Miha

AU - Tonks, Ian

AU - Stark, Mitchell

AU - Carrie, Dianne

AU - Mukhopadhyay, Pamela

AU - Seidel, Annica

AU - Ellis, Jonathan

AU - Deakin, Janine

AU - Wakefield, Matthew

AU - Krause, Lutz

AU - Blewitt, Marnie

AU - Kay, Graham

PY - 2013

Y1 - 2013

N2 - Background: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. Results: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdha, Pcdhß, and Pcdh?) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. Conclusions: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases.

AB - Background: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. Results: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdha, Pcdhß, and Pcdh?) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. Conclusions: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases.

KW - Clustered protocadherins

KW - Genomic imprinting

KW - Monoallelic expression

KW - Smchd1

KW - X inactivation.

U2 - 10.1186/1756-8935-6-19

DO - 10.1186/1756-8935-6-19

M3 - Article

VL - 6:19

SP - 1

EP - 16

JO - Epigenetics Chromatin

JF - Epigenetics Chromatin

SN - 1756-8935

ER -