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 revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels 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. [Display omitted] •DLX proteins modulate expression of GABAergic neuronal differentiation genes•DLXs drive a complex regulatory network by transcriptional activation and inhibition•Genomic and epigenomic context and sequence predict DLX effect on gene expression•DLX regulatory wiring may reflect general mechanisms implicated in neurodevelopment Lindtner et al. reveal the regulatory wiring organized by DLX transcription factors in forebrain GABAergic neuronal specification, by integrating functional genomic, epigenomic, and genetic data on a transgenic mouse model. This network determines key sequence-encoded regulatory elements and implicates a combination of histone modifications and biophysical interactions.