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Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation
Genes & Development ( IF 7.5 ) Pub Date : 2023-03-01 , DOI: 10.1101/gad.350269.122
Oana Păun 1 , Yu Xuan Tan 1 , Harshil Patel 2 , Stephanie Strohbuecker 2 , Avinash Ghanate 2 , Clementina Cobolli-Gigli 1 , Miriam Llorian Sopena 2 , Lina Gerontogianni 2 , Robert Goldstone 2 , Siew-Lan Ang 1 , François Guillemot 3 , Cristina Dias 3, 4
Affiliation  

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

中文翻译:


先锋因子ASCL1与远端调控元件mSWI/SNF复合体协同调节人神经分化



先锋转录因子被认为通过结合核小体 DNA 来激活基因表达,在发育过程中发挥关键作用,尽管先锋转录因子重塑染色质的机制仍不清楚。在这里,我们利用单细胞转录组学证明,神经源性转录因子 ASCL1(被认为是经典的先驱因子)的内源表达定义了人类神经分化中的瞬时祖细胞群。使用敲除模型来定义未结合状态来测试 ASCL1 的先锋功能,我们发现 ASCL1 的内源表达通过顺式调节驱动祖细胞分化,既作为经典先锋因子又作为非先锋重塑因子,其中 ASCL1 结合许可染色质以诱导染色质构象变化。 ASCL1 与 BAF SWI/SNF 染色质重塑复合物相互作用,主要在其充当非先锋因子的靶点上相互作用,并且我们提供了 ASCL1 和 SWI/SNF 共靶点子集上的共依赖性 DNA 结合和重塑的证据。我们的研究结果为 ASCL1 功能调节人类神经发生中远程调节元件的激活提供了新的见解,并揭示了其染色质重塑功能与伴侣 ATP 酶活性共同依赖的新机制。
更新日期:2023-03-01
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