From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo

The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant versus wild-type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its previously well-described role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from ‘permissive’ to ‘repressive’ nucleosome/chromatin organisation to maintain multipotency and define cell fates.

神经嵴（neural crest）是一类暂时存在的胚胎干细胞群体，以其多能性与广泛的发育潜能为特征。本研究针对foxd3突变型与野生型细胞开展体内神经嵴特异性转录组与表观基因组谱分析，以明确调控神经嵴特化的基因调控回路。结合foxd3生物素染色质免疫沉淀（biotin-ChIP）获得的全基因组结合分析，以及表达foxd3的迁移前神经嵴单细胞谱，本研究分析显示：在神经嵴形成的早期阶段，foxd3作为全局性先驱因子（pioneer factor），通过重塑染色质景观、开放顺式调控元件（cis-regulatory elements）并重组核小体，启动调控神经嵴特化与迁移的基因的表达。值得注意的是，foxd3随后会逐渐从转录激活因子转变为此前已有报道的转录抑制因子。综上，本研究结果证实，foxd3在神经嵴中以双模式发挥功能：作为"许可性"向"抑制性"核小体/染色质组织的开关，以维持细胞多能性并明确细胞命运。