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<p>Astrocytes are critical contributors to brain disorders, yet the mechanisms underlying their selective vulnerability to specific diseases remain poorly understood. Here, we demonstrate that NR3C1 acts as a key regulator of early postnatal astrocyte development, shaping long-term immune responses in mice. Through integrative analyses of gene expression, chromatin accessibility, and long-range chromatin interactions, we identify 55 stage-specific TFs, with NR3C1 uniquely associated with early postnatal maturation. Although mice lacking astrocytic NR3C1 exhibit no detectable developmental abnormalities, these mice display heightened susceptibility to exacerbated immune responses following adult-onset experimental autoimmune encephalomyelitis (EAE). Many of the dysregulated EAE response genes are linked to candidate <i>cis</i>-regulatory elements altered by early NR3C1 loss, driving exacerbated inflammatory responses. Notably, only NR3C1 depletion during early, but not late, astrocyte development induces long-lasting epigenetic reprogramming that primes astrocytic immune responses.</p>

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NR3C1-mediated epigenetic regulation suppresses astrocytic immune responses in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月22日

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  • Seongwan Park,
  • Hyeonji Park,
  • Youkyeong Gloria Byun,
  • Xiaolin Wei,
  • Junghyun Eom,
  • Jaegeon Joo,
  • Andrew J. Lee,
  • Yarui Diao,
  • Won-Suk Chung,
  • Inkyung Jung

摘要

Astrocytes are critical contributors to brain disorders, yet the mechanisms underlying their selective vulnerability to specific diseases remain poorly understood. Here, we demonstrate that NR3C1 acts as a key regulator of early postnatal astrocyte development, shaping long-term immune responses in mice. Through integrative analyses of gene expression, chromatin accessibility, and long-range chromatin interactions, we identify 55 stage-specific TFs, with NR3C1 uniquely associated with early postnatal maturation. Although mice lacking astrocytic NR3C1 exhibit no detectable developmental abnormalities, these mice display heightened susceptibility to exacerbated immune responses following adult-onset experimental autoimmune encephalomyelitis (EAE). Many of the dysregulated EAE response genes are linked to candidate cis-regulatory elements altered by early NR3C1 loss, driving exacerbated inflammatory responses. Notably, only NR3C1 depletion during early, but not late, astrocyte development induces long-lasting epigenetic reprogramming that primes astrocytic immune responses.