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Cell Rep. 2019 Aug 20;28(8):2048-2063.e8. doi: 10.1016/j.celrep.2019.07.022.

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

Author information

1
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Neurobiology, Physiology and Behavior, and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95618, USA.
3
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Development and Stem Cell Biology Program, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
5
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA.
7
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, Merced, CA 95343, USA.
8
Department of Neurobiology, Physiology and Behavior, and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95618, USA. Electronic address: asnord@ucdavis.edu.
9
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Development and Stem Cell Biology Program, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: john.rubenstein@ucsf.edu.

Abstract

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.

KEYWORDS:

ChIP-seq; DLX; GABA neuron; basal ganglia; chromatin; development; enhancers; ganglionic eminence; genome; histone; regulatory element; telencephalon; transcription factor; transcriptional circuits

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