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Background <p>Stem cell maintenance and lineage commitment in the nervous system require precise regulation of transcription factors, with SOX2 serving as a pivotal regulator. SOX2 expression is controlled by multiple enhancers, including the <i>Sox2</i> regulatory region 2 (<i>Srr2</i>). However, the specific role of <i>Srr2</i> in adult neurogenesis and chromatin regulation during neural lineage commitment remains incompletely understood.</p> Results <p>To dissect the function of <i>Srr2</i>, we generate a CRISPR-Cas9 mouse model harboring a targeted deletion of this enhancer. <i>Srr2</i> deletion reduce SOX2 levels in proliferating, but not differentiating, neurosphere cultures, while impairing both neuronal and oligodendroglial differentiation. Paired bulk RNA-seq and ATAC-seq during proliferation and early differentiation reveal that loss of <i>Srr2</i> induces widespread chromatin compaction during proliferation, which partially converges toward wild-type states upon early differentiation. Multi-omic integration identifies a subset of neurogenic genes exhibiting persistent promoter closure and impaired transcriptional induction in proliferating mutant cells, despite being normally translated during neural differentiation. In vivo, subependymal zone cells of <i>Srr2</i><sup><i>del/del</i></sup> mice exhibit lower SOX2 and FOXG1 expression, fewer ASCL1/OLIG2 progenitors, and reduced neuronal and oligodendroglial marker expression.</p> Conclusions <p>These findings establish <i>Srr2</i> as a critical enhancer of <i>Sox2</i> required to maintain a chromatin environment permissive for neural differentiation during stem cell proliferation. Our study underscores the essential role of non-coding regulatory elements in coordinating chromatin accessibility, transcriptional programs, and stem cell fate decisions during adult neurogenesis.</p>

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Srr2-dependent SOX2 levels govern the chromatin and transcriptional landscape of adult neural stem cell fate decisions in mouse

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Sara Cruces-Salguero,
  • Antonio Jordán-Pla,
  • Ana Domingo-Muelas,
  • Jose Manuel Morante-Redolat,
  • Karine Rizzoti,
  • Ander Matheu,
  • Isabel Fariñas,
  • Robin Lovell-Badge,
  • Veronica Moncho-Amor

摘要

Background

Stem cell maintenance and lineage commitment in the nervous system require precise regulation of transcription factors, with SOX2 serving as a pivotal regulator. SOX2 expression is controlled by multiple enhancers, including the Sox2 regulatory region 2 (Srr2). However, the specific role of Srr2 in adult neurogenesis and chromatin regulation during neural lineage commitment remains incompletely understood.

Results

To dissect the function of Srr2, we generate a CRISPR-Cas9 mouse model harboring a targeted deletion of this enhancer. Srr2 deletion reduce SOX2 levels in proliferating, but not differentiating, neurosphere cultures, while impairing both neuronal and oligodendroglial differentiation. Paired bulk RNA-seq and ATAC-seq during proliferation and early differentiation reveal that loss of Srr2 induces widespread chromatin compaction during proliferation, which partially converges toward wild-type states upon early differentiation. Multi-omic integration identifies a subset of neurogenic genes exhibiting persistent promoter closure and impaired transcriptional induction in proliferating mutant cells, despite being normally translated during neural differentiation. In vivo, subependymal zone cells of Srr2del/del mice exhibit lower SOX2 and FOXG1 expression, fewer ASCL1/OLIG2 progenitors, and reduced neuronal and oligodendroglial marker expression.

Conclusions

These findings establish Srr2 as a critical enhancer of Sox2 required to maintain a chromatin environment permissive for neural differentiation during stem cell proliferation. Our study underscores the essential role of non-coding regulatory elements in coordinating chromatin accessibility, transcriptional programs, and stem cell fate decisions during adult neurogenesis.