Dataset Information

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.

ABSTRACT: X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

SUBMITTER: Luijk R

PROVIDER: S-EPMC6138682 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.

Luijk René R Wu Haoyu H Ward-Caviness Cavin K CK Hannon Eilis E Carnero-Montoro Elena E Min Josine L JL Mandaviya Pooja P Müller-Nurasyid Martina M Mei Hailiang H van der Maarel Silvere M SM Relton Caroline C Mill Jonathan J Waldenberger Melanie M Bell Jordana T JT Jansen Rick R Zhernakova Alexandra A Franke Lude L 't Hoen Peter A C PAC Boomsma Dorret I DI van Duijn Cornelia M CM van Greevenbroek Marleen M J MMJ Veldink Jan H JH Wijmenga Cisca C van Meurs Joyce J Daxinger Lucia L Slagboom P Eline PE van Zwet Erik W EW Heijmans Bastiaan T BT

Nature communications 20180914 1

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific ch ...[more]

PMID: 30218040

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Project description:BackgroundX-chromosome inactivation (XCI) is a mechanism in which one of two X chromosomes in females is randomly inactivated in order to compensate for imbalance of gene dosage between sexes. However, about 15% of genes on the inactivated X chromosome (Xi) escape from XCI. The methylation level of the promoter region of the escape gene is lower than that of the inactivated genes. Dxz4 and/or Firre have critical roles for forming the three-dimensional (3D) structure of Xi. In mice, disrupting the 3D structure of Xi by deleting both Dxz4 and Firre genes led to changing of the escape genes list. To estimate the impact for escape genes by X-chromosome rearrangements, including DXZ4 and FIRRE, we examined the methylation status of escape gene promoters in patients with various X-chromosome rearrangements.ResultsTo detect the breakpoints, we first performed array-based comparative genomic hybridization and whole-genome sequencing in four patients with X-chromosome rearrangements. Subsequently, we conducted array-based methylation analysis and reduced representation bisulfite sequencing in the four patients with X-chromosome rearrangements and controls. Of genes reported as escape genes by gene expression analysis using human hybrid cells in a previous study, 32 genes showed hypomethylation of the promoter region in both male controls and female controls. Three patients with X-chromosome rearrangements had no escape genes with abnormal methylation of the promoter region. One of four patients with the most complicated rearrangements exhibited abnormal methylation in three escape genes. Furthermore, in the patient with the deletion of the FIRRE gene and the duplication of DXZ4, most escape genes remained hypomethylated.ConclusionX-chromosome rearrangements are unlikely to affect the methylation status of the promoter regions of escape genes, except for a specific case with highly complex rearrangements, including the deletion of the FIRRE gene and the duplication of DXZ4.

Dataset Information

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.

Publications

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.

Similar Datasets

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