Genomic Resolution of DLX-orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This elucidated the DLX-organized gene regulatory network at genomic, cellular, and spatial level in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment. Regulatory wiring of early telencephalic GABAergic neuron development organized by DLX family transcription factors, integrating in situ hybridization, transcriptomic, and epigenomic data from wild-type and Dlx1/2 knockout ganglionic eminences (embryonic mouse basal ganglia (BG))DLX转录因子（transcription factors, TFs）是脊椎动物大脑发育过程中的核心调控因子，可驱动前脑γ-氨基丁酸能神经元的分化。敲除Dlx1与Dlx2基因会改变对前脑γ-氨基丁酸能发育至关重要的基因的表达水平。本研究整合了表观基因组学与转录组学分析，并辅以原位杂交（in situ hybridization, ISH）以及调控元件（regulatory element, RE）功能的体内与体外实验研究，阐明了小鼠胚胎基底神经节中由DLX转录因子构建的基因调控网络在基因组、细胞及空间三个维度的特征。DLX转录因子兼具激活与抑制的双重调控功能，其结合靶基因座后的调控效应由靶位点的序列特征与基因组背景共同决定。本研究结果揭示并部分解释了一个看似矛盾的现象：DLX结合位点广泛分布，但在表观基因组与转录组层面上，仅少数靶基因座对Dlx1与Dlx2的敲除敏感。本研究中鉴定出的DLX转录因子调控特性，为转录因子如何调控神经发育背后的动态表达程序提供了普适性机制的借鉴。本数据集涵盖了由DLX家族转录因子调控的早期端脑γ-氨基丁酸能神经元发育的调控网络信息，整合了野生型与Dlx1/2基因敲除神经节隆起（即小鼠胚胎基底神经节，BG）的原位杂交、转录组学及表观基因组学数据。