Abstract:
Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated in Smarcc1 conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.
摘要:
对Hedgehog(HH)信号通路的转录反应主要由小鼠肢体中的GLI抑制调节。先前的研究表明BAF染色质重塑复合物在介导GLI抑制中的作用。与这种可能性一致,核心BAF复合物蛋白SMARCC1存在于大多数活跃的肢体增强剂,包括大多数GLI增强剂。然而,与降低染色质可及性的GLI抑制相反,SMARCC1在大多数增强剂中保持染色质可及性,包括那些受GLI约束的人。此外,SMARCC1在GLI调节的增强子上的结合独立于GLI3发生。与以前的研究一致,一些单独的GLI靶基因在Smarcc1条件性敲除中被错误调节,尽管大多数GLI靶基因不受影响。此外,SMARCC1对于介导HH突变肢芽中的组成型GLI抑制不是必需的。我们得出结论,SMARCC1不介导GLI3抑制,我们建议利用替代染色质重塑复合物。