Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation.
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.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, Molecular Epigenetics Group, Life Sciences Institute, Vancouver, BC, Canada V6T 1Z3.
Allison M
AM
Cotton
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada V5Z 4H4, The Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4.
E Magda
EM
Price
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, The Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4 Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada V5Z 4H4.
Meaghan J
MJ
Jones
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, Molecular Epigenetics Group, Life Sciences Institute, Vancouver, BC, Canada V6T 1Z3.
Bradley P
BP
Balaton
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, The Child and Family Research Institute, Vancouver, BC, Canada V5Z 4H4 Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada V5Z 4H4.
Michael S
MS
Kobor
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3, Molecular Epigenetics Group, Life Sciences Institute, Vancouver, BC, Canada V6T 1Z3, carolyn.brown@ubc.ca.
Carolyn J
CJ
Brown
D002843:Chromatin / Q000378:metabolism*; D041321:Chromosomes, Human, X; D018899:CpG Islands; D019175:DNA Methylation; D021901:DNA, Intergenic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation
D002843:Chromatin; D021901:DNA, Intergenic