{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "College of Computing, Georgia Institute of Technology, Atlanta, GA 30332",
    "Current address: Arbor Biotechnologies, Cambridge, MA, 02140",
    "School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332",
    "Department of Ecology and Evolution and Marine Biology, Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara",
    "Current address: Foundation Medicine, Inc., Boston, MA, 02210",
    "Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain",
    "Ikerbasque, Basque Foundation for Science, Bilbao, Spain",
    "Translational prostate cancer Research lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Derio, Spain"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Robert Morgan"
    },
    {
      "affs": [
        3
      ],
      "name": "E. Loh"
    },
    {
      "affs": [
        4,
        2
      ],
      "name": "Devika Singh",
      "orcid": "0000-0001-9560-2079"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Isabel Mendizabal",
      "orcid": "0000-0002-9018-3474"
    },
    {
      "affs": [
        3
      ],
      "name": "Soojin V. Yi",
      "orcid": "0000-0003-1497-1871"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dbq302y1zjcm9.bib",
  "cited_by": 12,
  "doi": "10.1186/s13072-026-00705-x",
  "fulltext_url": null,
  "id": "dbq302y1zjcm9",
  "issns": [
    "1756-8935"
  ],
  "landing_url": "https://doi.org/10.1186/s13072-026-00705-x",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Epigenetics and DNA Methylation"
    ]
  ],
  "openalex": "W7221083755",
  "pdf_url": null,
  "pmcid": "PMC11042362",
  "pmid": "38659923",
  "published": "2026-10-09",
  "publisher": "BioMed Central",
  "ris": "https://research.draconitic.com/paper/dbq302y1zjcm9.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:06Z",
      "native_id": "W7221083755",
      "source": "openalex",
      "url": "https://doi.org/10.1186/s13072-026-00705-x"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Epigenetics and DNA Methylation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "DNA methylation differences between female and male X chromosomes in human brain",
  "title_text": "DNA methylation differences between female and male X chromosomes in human brain",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:07Z",
  "url": "https://research.draconitic.com/paper/dbq302y1zjcm9",
  "venue": "Epigenetics & Chromatin",
  "versions": []
}