DNA methylation differences between female and male X chromosomes in human brain
8 affiliations
- 1College of Computing, Georgia Institute of Technology, Atlanta, GA 30332
- 2Current address: Arbor Biotechnologies, Cambridge, MA, 02140
- 3School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
- 4Department of Ecology and Evolution and Marine Biology, Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara
- 5Current address: Foundation Medicine, Inc., Boston, MA, 02210
- 6Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain
- 7Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- 8Translational prostate cancer Research lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Derio, Spain
Abstract
Background DNA methylation is a key epigenetic mechanism of sex chromosome regulation. However, DNA methylation studies often exclude X chromosomes. Moreover, widely used DNA methylation assays interrogate biased subsets of CpGs, rather than assessing CpGs across the whole chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Results Here we addressed this gap of knowledge by investigating X chromosome DNA methylation in 89 whole genome methylomes from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that the combined methylation of the female X chromosomes is globally reduced (hypomethylated) across the chromosome compared with the male X and autosomes. DNA methylation patterns of promoters are more heterogeneous; while many promoters are more highly methylated (hypermethylated) in female X than in male X, a substantial number of promoters exhibit female hypomethylation. Notably, promoters of genes with higher expression in females—used here as a proxy for those that escape X chromosome inactivation—are significantly enriched among female hypomethylated promoters. Differentially methylated regions across the whole X chromosome corroborate the pervasive chromosome-wide reduction in the combined female X methylation and reveal many cell-type and sex-differentiated regions. Mechanistically, we show that female hyper- and hypo-methylation of promoters in large part associate with low and high density CpG promoters that tend to be highly and lowly methylated, respectively. Conclusions These results provide chromosome-wide evidence that, in the examined human brain cell types, the combined female X chromosome methylation level is globally lower than that of the male X chromosome. More broadly, our findings support a model where relative hypomethylation is a general feature of transcriptionally inactive genomic regions compared to active genomic regions. Furthermore, we show that DNA methylation-mediated silencing of X chromosomes may preferentially occur in a subset of promoters with distinctive genomic and epigenetic features. This study provides a comprehensive and novel list of sex differentiated genomic regions on the X chromosome and furthers our understanding of epigenetic regulation of X chromosomes.
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BibTeX
@article{morgan2026methylation,
title = {{DNA methylation differences between female and male X chromosomes in human brain}},
author = {Robert Morgan and E. Loh and Devika Singh and Isabel Mendizabal and Soojin V. Yi},
journal = {Epigenetics \& Chromatin},
year = {2026},
month = oct,
doi = {10.1186/s13072-026-00705-x},
url = {https://doi.org/10.1186/s13072-026-00705-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - DNA methylation differences between female and male X chromosomes in human brain
AU - Robert Morgan
AU - E. Loh
AU - Devika Singh
AU - Isabel Mendizabal
AU - Soojin V. Yi
PY - 2026
DA - 2026/10/09
JO - Epigenetics & Chromatin
DO - 10.1186/s13072-026-00705-x
UR - https://doi.org/10.1186/s13072-026-00705-x
AB - Background DNA methylation is a key epigenetic mechanism of sex chromosome regulation. However, DNA methylation studies often exclude X chromosomes. Moreover, widely used DNA methylation assays interrogate biased subsets of CpGs, rather than assessing CpGs across the whole chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Results Here we addressed this gap of knowledge by investigating X chromosome DNA methylation in 89 whole genome methylomes from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that the combined methylation of the female X chromosomes is globally reduced (hypomethylated) across the chromosome compared with the male X and autosomes. DNA methylation patterns of promoters are more heterogeneous; while many promoters are more highly methylated (hypermethylated) in female X than in male X, a substantial number of promoters exhibit female hypomethylation. Notably, promoters of genes with higher expression in females—used here as a proxy for those that escape X chromosome inactivation—are significantly enriched among female hypomethylated promoters. Differentially methylated regions across the whole X chromosome corroborate the pervasive chromosome-wide reduction in the combined female X methylation and reveal many cell-type and sex-differentiated regions. Mechanistically, we show that female hyper- and hypo-methylation of promoters in large part associate with low and high density CpG promoters that tend to be highly and lowly methylated, respectively. Conclusions These results provide chromosome-wide evidence that, in the examined human brain cell types, the combined female X chromosome methylation level is globally lower than that of the male X chromosome. More broadly, our findings support a model where relative hypomethylation is a general feature of transcriptionally inactive genomic regions compared to active genomic regions. Furthermore, we show that DNA methylation-mediated silencing of X chromosomes may preferentially occur in a subset of promoters with distinctive genomic and epigenetic features. This study provides a comprehensive and novel list of sex differentiated genomic regions on the X chromosome and furthers our understanding of epigenetic regulation of X chromosomes.
SN - 1756-8935
ER -