Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete

Johnston, C L; Lovell, Frances L; Leongamornlert, Daniel; Stranger, Barbara Elaine; Dermitzakis, Emmanouil T.; Ross, Mark T.

doi:10.1371/journal.pgen.0040009

Cited by 133 publications

(148 citation statements)

References 34 publications

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“…Of the other 26 genes, NLGN4X, PCDH11X, TBL1X, and TXLNG have functional Y-homologs, STS and KAL1 have pseudogene Y-homologs, and PLCXD1 is located in the Xp pseudo-autosomal region, all of which are features shared by many other genes that are known to escape XCI. In addition, 14 of these 31 genes were highlighted as potentially escaping XCI based on their consistently higher expression in females versus males ( Johnston et al 2008), and two were also previously identified as likely escaping XCI due to a lack of promoter methylation in females (Yasukochi et al 2010). We conclude that the use of comparative methylation profiling provides a powerful method for the classification of genes escaping XCI that is complementary to methods based on expression profiling.…”

Section: Discussionmentioning

confidence: 79%

DNA methylation profiles of human active and inactive X chromosomes

Sharp¹,

Stathaki²,

Migliavacca³

et al. 2011

Genome Res.

261

194

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X-chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. To characterize epigenetic changes that accompany this process, we measured DNA methylation levels in 45,X patients carrying a single active X chromosome (X a ), and in normal females, who carry one X a and one inactive X (X i ). Methylated DNA was immunoprecipitated and hybridized to high-density oligonucleotide arrays covering the X chromosome, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands (CGIs). While the majority of CGIs show increased methylation levels on the X i , XCI actually results in significant reductions in methylation at 7% of CGIs. Both intraand inter-genic CGIs undergo epigenetic modification, with the biggest increase in methylation occurring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI generally have low levels of promoter methylation, while genes that show inter-individual variation in silencing show intermediate increases in methylation. Thus, promoter methylation and susceptibility to XCI are correlated. We also observed a global correlation between CGI methylation and the evolutionary age of X-chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We used our epigenetic map to predict 26 novel genes escaping XCI, and searched for parent-of-origin-specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides a detailed analysis of the epigenetic profile of active and inactive X chromosomes.[Supplemental material is available for this article.] X-chromosome inactivation (XCI) is a mechanism of dosage compensation that equalizes the expression of sex-linked genes between 46,XY males and 46,XX females (Lyon 1961). This results in the silencing of the majority of genes on one of the two X chromosomes in each somatic cell of females (Carrel and Willard 2005) and a transition to a heterochromatic state. XCI is accompanied by several epigenetic modifications to the inactive X (X i ), such as an accumulation of variant histones and transcripts from the XIST gene (Clemson et al. 1996;Costanzi and Pehrson 1998), a delay in replication timing (Willard and Latt 1976), and relocalization to the nuclear periphery (Barr and Bertram 1949).Several studies have shown that DNA methylation of the X i plays an important role in the maintenance of its inactive state. While the active X (X a ) and X i have very similar global levels of methylation (Bernadino et al. 1996), studies have shown that CpG islands (CGIs) have a tendency to be methylated on the X i and unmethylated on the X a (Tribioli et al. 1992;Hellman and Chess 2007). In contrast, the CGIs of genes escaping XCI often remain unmethylated on both the X i and X a (Weber et al. 2007). Mouse knockouts for the DNA methyltransferase enzyme Dnmt1 show defects in X inactivat...

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Section: Discussionmentioning

confidence: 79%

DNA methylation profiles of human active and inactive X chromosomes

Sharp¹,

Stathaki²,

Migliavacca³

et al. 2011

Genome Res.

261

194

View full text Add to dashboard Cite

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“…However, expression is not doubled in females, consistent with our RNA-seq data, in which ratios between BL6 and spretus reads were lower than 1, except for Xist, Mid1, and 6720401G13Rik. Similarly, human escape genes show a relatively modest increase in expression in female versus male cell lines, suggesting lower expression from the inactive X (Carrel and Willard 2005;Johnston et al 2008). …”

Section: Discussionmentioning

confidence: 99%

Global survey of escape from X inactivation by RNA-sequencing in mouse

Yang¹,

Babak²,

Shendure³

et al. 2010

Genome Res.

318

400

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X inactivation equalizes the dosage of gene expression between the sexes, but some genes escape silencing and are thus expressed from both alleles in females. To survey X inactivation and escape in mouse, we performed RNA sequencing in Mus musculus × Mus spretus cells with complete skewing of X inactivation, relying on expression of single nucleotide polymorphisms to discriminate allelic origin. Thirteen of 393 (3.3%) mouse genes had significant expression from the inactive X, including eight novel escape genes. We estimate that mice have significantly fewer escape genes compared with humans. Furthermore, escape genes did not cluster in mouse, unlike the large escape domains in human, suggesting that expression is controlled at the level of individual genes. Our findings are consistent with the striking differences in phenotypes between female mice and women with a single X chromosome—a near normal phenotype in mice versus Turner syndrome and multiple abnormalities in humans. We found that escape genes are marked by the absence of trimethylation at lysine 27 of histone H3, a chromatin modification associated with genes subject to X inactivation. Furthermore, this epigenetic mark is developmentally regulated for some mouse genes.

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“…The reason for the incomplete inactivation of two genes (UBE2A and SAT1) is unclear. The degree of completion of XCI in adult tissues varies among studies depending on the tissue (Talebizadeh et al 2006), from 5.4% of X-linked genes with increased female expression in human lymphoblastoid cell lines (Johnston et al 2008) to 15-25% in fibroblasts and hybrid cells (Carrel & Willard 2005), and the distribution of genes that escape inactivation has been found not to be random along Sexual dimorphism in elongating bovine embryos the chromosome, but rather clustered and mapping primarily to the distal portion of the X chromosome short arm (Xp) (Miller & Willard 1998, Carrel & Willard 2005, far from the XIST gene (Huynh & Lee 2003). However, we could not establish a relation between linear distribution and escape from inactivation, which may be caused by the three-dimensional structure of the chromosome or by gene-specific regulation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

Bermejo-Álvarez¹,

Rizos²,

Lonergan³

et al. 2011

Reproduction

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Sex chromosome transcripts can lead to a broad transcriptional sexual dimorphism in the absence of concomitant or previous exposure to sex hormones, especially when X-chromosome inactivation (XCI) is not complete. XCI timing has been suggested to differ greatly among species, and in bovine, most of the X-linked transcripts are upregulated in female blastocysts. To determine the timing of XCI, we analyzed in day 14 bovine embryos the sexual dimorphic transcription of seven X-linked genes known to be upregulated in female blastocysts (X24112, brain-expressed X-linked 2 (BEX2), ubiquitin-conjugating enzyme E2A (UBE2A), glucose-6-phosphate dehydrogenase (G6PD), brain-expressed X-linked 1 (BEX1), calpain 6 (CAPN6), and spermidine/spermine N-acetyltransferase 1 (SAT1)). The transcription of five genes whose expression differs between sexes at the blastocyst stage (DNMT3A, interferon tau (IFNT2), glutathione S-transferase mu 3 (GSTM3), progesterone receptor membrane component 1 (PGRMC1), and laminin alpha 1 (LAMA1)) and four genes related with sex determination (Wilms tumor 1 (WT1), gata binding protein 4 (GATA4), zinc finger protein multitype 2 (ZFPM2), and DMRT1) was also analyzed to determine the evolution of transcriptional sexual dimorphism. The expression level of five X-linked transcripts was effectively equalized among sexes suggesting that, in cattle, a substantial XCI occurs during the period between blastocyst hatching and initiation of elongation, although UBE2A and SAT1 displayed significant transcriptional differences. Similarly, sexual dimorphism was also reduced for autosomal genes with only DNMT3A and IFNT2 exhibiting sex-related differences. Among the genes potentially involved in sex determination, Wilms tumor 1 (WT1) was significantly upregulated in males and GATA4 in females, whereas no differences were observed for ZFPM2 and DMRT1. In conclusion, a major XCI occurred between the blastocyst and early elongation stages leading to a reduction in the transcriptional sexual dimorphism of autosomal genes, which makes the period the most susceptible to sex-specific embryo loss.

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Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete

Cited by 133 publications

References 34 publications

DNA methylation profiles of human active and inactive X chromosomes

DNA methylation profiles of human active and inactive X chromosomes

Global survey of escape from X inactivation by RNA-sequencing in mouse

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

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