Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation
Open Access
- 7 November 2014
- journal article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 24 (6), 1528-1539
- https://doi.org/10.1093/hmg/ddu564
Abstract
X-chromosome inactivation (XCI) achieves dosage compensation between males and females through the silencing of the majority of genes on one of the female X chromosomes. Thus, the female X chromosomes provide a unique opportunity to study euchromatin and heterochromatin of allelic regions within the same nuclear environment. We examined the interplay of DNA methylation (DNAm) with CpG density, transcriptional activity and chromatin state at genes on the X chromosome using over 1800 female samples analysed with the Illumina Infinium Human Methylation450 BeadChip. DNAm was used to predict an inactivation status for 63 novel transcription start sites (TSSs) across 27 tissues. There was high concordance of inactivation status across tissues, with 62% of TSSs subject to XCI in all 27 tissues examined, whereas 9% escaped from XCI in all tissues, and the remainder showed variable escape from XCI between females in subsets of tissues. Inter-female and twin data supported a model of predominately cis-acting influences on inactivation status. The level of expression from the inactive X relative to the active X correlated with the amount of female promoter DNAm to a threshold of ∼30%, beyond which genes were consistently subject to inactivation. The inactive X showed lower DNAm than the active X at intragenic and intergenic regions for genes subject to XCI, but not at genes that escape from inactivation. Our categorization of genes that escape from X inactivation provides candidates for sex-specific differences in disease.Keywords
This publication has 53 references indexed in Scilit:
- Landscape of transcription in human cellsNature, 2012
- Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X ChromosomeDevelopmental Cell, 2012
- Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivationHuman Genetics, 2011
- Mapping and analysis of chromatin state dynamics in nine human cell typesNature, 2011
- Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblastsNature Genetics, 2009
- The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shoresNature Genetics, 2009
- Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genomeNature Genetics, 2007
- A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promotersProceedings of the National Academy of Sciences of the United States of America, 2006
- Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cellsNature Genetics, 2005
- X-inactivation profile reveals extensive variability in X-linked gene expression in femalesNature, 2005