{
  "abstract": "Background: Autism spectrum disorder (ASD) shows a strong male bias (~4:1). CHD8, a frequently mutated ASD gene, regulates neuronal development and Xist regulation in X-chromosome inactivation (XCI). However, its role in female neurodevelopment remains poorly understood due to the predominance of male-derived or sex-agnostic models. Methods: We performed integrated multi-omics analysis of female mouse embryonic stem cells (ES) differentiating to neuronal progenitor cells (NPCs) using wild-type, CHD8 knockdown (KD), knockout (KO), and domain-specific rescue lines (full-length, {Delta}Chromo, {Delta}Helicase). RNA-seq, CHD8 and H3K4me3 ChIP-seq, and ATAC-seq datasets were integrated to assess transcriptional, chromatin-binding and -accessibility changes during differentiation. Results: CHD8 occupancy was substantially remodelled during female neuronal differentiation, with 3,754 genes gaining NPCs-specific CHD8 binding predominantly at distal regulatory elements. CHD8 loss dysregulated 2,752 genes (1,134 upregulated and 1,618 downregulated), in NPCs. Differential accessibility analysis identified 4,486 chromatin regions with significant CHD8-dependent changes. Domain-specific rescue experiments showed that chromodomain and helicase activity makes distinct, non-redundant contributions to transcriptional recovery: {Delta}Chromo-rescued only ~ 1.0% of CHD8-dependent transcriptional changes, {Delta}Helicase rescued ~ 41.1%, and full-length CHD8 rescued ~ 70%. Integration of binding, expression, and accessibility data identified 8 high-confidence direct CHD8 target genes, and cross-referencing with the SFARI Autism Risk Gene database revealed that CHD8-dependent transcriptional changes converge on autism-related pathways. Conclusions: CHD8 acts as a key regulator of female-derived neuronal differentiation, recruited to H3K4me3-marked promoters in a chromodomain-dependent manner, with helicase activity providing non-redundant regulatory capacity at a subset of targets. These findings provide a molecular framework for CHD8-dependent transcriptional regulation in female NPCs and underscore the importance of including female-derived systems in neurodevelopmental disorder research.",
  "abstract_shown": true,
  "affiliations": [
    "Unit of Cell and Developmental Biology, Department of Biology, University of Pisa Strada Statale dell Abetone e Brennero 4, 56123, Pisa, Italy"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "A. K. Danga"
    },
    {
      "name": "A. Colantoni"
    },
    {
      "name": "N. Pomella"
    },
    {
      "name": "N. R. Blanes"
    },
    {
      "name": "M. Genovesi"
    },
    {
      "name": "F. Ersoz"
    },
    {
      "name": "G. G. Tartaglia"
    },
    {
      "name": "M. M. Fakhry"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Cerase"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5wags7aapax8y.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.09.750428",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.09.750428v1.full",
  "id": "5wags7aapax8y",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.09.750428v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1311|Genetics and Neurodevelopmental Disorders"
    ]
  ],
  "openalex": "W7212157044",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.09.750428v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5wags7aapax8y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:58Z",
      "native_id": "10.64898/2026.09.09.750428",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.09.750428v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "CHD8 orchestrates chromatin landscapes during early female neuronal differentiation",
  "title_text": "CHD8 orchestrates chromatin landscapes during early female neuronal differentiation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:58Z",
  "url": "https://research.draconitic.com/paper/5wags7aapax8y",
  "venue": "bioRxiv",
  "versions": []
}