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<p>Little is known about how three-dimensional chromatin topology shapes mammalian craniofacial development. In mouse cranial neural crest cells, a Polycomb Repressive Complex 2 (PRC2)-dependent chromatin architecture is established before migration. This configuration maintains craniofacial gene promoters poised and connects them with distal Polycomb tethering elements, positioning promoters in spatial proximity to future long-range enhancers. Deletion of <i>Ezh2</i> disrupts this early topology, causing inappropriate gene derepression in post-migratory craniofacial subpopulations where these genes are normally silenced, and failure of long-range enhancer recruitment where activation is required, thereby impairing proper gene expression. We further identify a distal Polycomb tethering element essential for <i>Hoxa2</i> enhancer recruitment across topologically associating domains. Thus, Polycomb acts not only as a transcriptional repressor, but also as a chromatin-folding organizer that prepares developmental genes for later activation, by facilitating subsequent recruitment of distal active enhancers previously not in contact. Polycomb-mediated topology therefore orchestrates the transition from progenitor plasticity to precise spatiotemporal control of morphogenetic gene programs during neural crest development and face formation.</p>

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Polycomb chromatin topology enables long-range enhancer recruitment during craniofacial development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Yousra Ben Zouari,
  • Onkar Joshi,
  • Adwait Salvi,
  • Sandra Kessler,
  • Sebastien Ducret,
  • Fiona Ross,
  • Sjoerd J. B. Holwerda,
  • Nathalie Vilain,
  • Soujanya Mamilla-Sanivaram,
  • Sebastien Smallwood,
  • Hubertus Kohler,
  • Michael B. Stadler,
  • Maryline Minoux,
  • Filippo M. Rijli

摘要

Little is known about how three-dimensional chromatin topology shapes mammalian craniofacial development. In mouse cranial neural crest cells, a Polycomb Repressive Complex 2 (PRC2)-dependent chromatin architecture is established before migration. This configuration maintains craniofacial gene promoters poised and connects them with distal Polycomb tethering elements, positioning promoters in spatial proximity to future long-range enhancers. Deletion of Ezh2 disrupts this early topology, causing inappropriate gene derepression in post-migratory craniofacial subpopulations where these genes are normally silenced, and failure of long-range enhancer recruitment where activation is required, thereby impairing proper gene expression. We further identify a distal Polycomb tethering element essential for Hoxa2 enhancer recruitment across topologically associating domains. Thus, Polycomb acts not only as a transcriptional repressor, but also as a chromatin-folding organizer that prepares developmental genes for later activation, by facilitating subsequent recruitment of distal active enhancers previously not in contact. Polycomb-mediated topology therefore orchestrates the transition from progenitor plasticity to precise spatiotemporal control of morphogenetic gene programs during neural crest development and face formation.