Transcription factors (TFs) bind combinatorially to cis-regulatory elements, orchestrating transcriptional programs. Although studies of chromatin state and chromosomal interactions have demonstrated dynamic neurodevelopmental cis-regulatory landscapes, parallel understanding of TF interactions lags. To elucidate combinatorial TF binding driving mouse basal ganglia development, we integrated chromatin immunoprecipitation sequencing (ChIP-seq) for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and gene expression data, and functional enhancer assays. We identified sets of putative regulatory elements with shared TF binding (TF-pRE modules) that orchestrate distinct processes of GABAergic neurogenesis and suppress other cell fates. The majority of pREs were bound by one or two TFs; however, a small proportion were extensively bound. These sequences had exceptional evolutionary conservation and motif density, complex chromosomal interactions, and activity as in vivo enhancers. Our results provide insights into the combinatorial TF-pRE interactions that activate and repress expression programs during telencephalon neurogenesis and demonstrate the value of TF binding toward modeling developmental transcriptional wiring.

中文翻译：

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组合转录因子结合编码小鼠前脑 GABA 能神经发生的顺式调节布线


转录因子 （TFs） 与顺式调节元件组合结合，编排转录程序。尽管对染色质状态和染色体相互作用的研究已经证明了动态的神经发育顺式调节景观，但对 TF 相互作用的平行理解滞后。为了阐明驱动小鼠基底神经节发育的组合 TF 结合，我们整合了 12 个 TF 的染色质免疫沉淀测序 （ChIP-seq）、H3K4me3 相关的增强子-启动子相互作用、染色质和基因表达数据以及功能增强子测定。我们确定了一组具有共享 TF 结合 （TF-pRE 模块） 的假定调节元件，这些元件协调 GABA 能神经发生的不同过程并抑制其他细胞命运。大多数 pRE 由一个或两个 TF 结合;然而，一小部分被广泛装订。这些序列具有特殊的进化保守性和基序密度、复杂的染色体相互作用以及体内增强子的 活性。我们的结果提供了对端脑神经发生过程中激活和抑制表达程序的组合 TF-pRE 相互作用的见解，并证明了 TF 结合对建模发育转录布线的价值。