Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons
Susan Lindtner,
Rinaldo Catta-Preta,
Hua Tian,
Linda Su-Feher,
James D. Price,
Diane E. Dickel,
Vanille Greiner,
Shanni N. Silberberg,
Gabriel L. McKinsey,
Michael T. McManus,
Len A. Pennacchio,
Axel Visel,
Alex S. Nord,
John L.R. Rubenstein
Affiliations
Susan Lindtner
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Rinaldo Catta-Preta
Department of Neurobiology, Physiology and Behavior, and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95618, USA
Hua Tian
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Linda Su-Feher
Department of Neurobiology, Physiology and Behavior, and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95618, USA
James D. Price
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
Diane E. Dickel
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Vanille Greiner
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA
Shanni N. Silberberg
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Gabriel L. McKinsey
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Michael T. McManus
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA
Len A. Pennacchio
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
Axel Visel
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
Alex S. Nord
Department of Neurobiology, Physiology and Behavior, and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95618, USA; Corresponding author
John L.R. Rubenstein
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; Corresponding author
Summary: 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. : 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. Keywords: DLX, transcription factor, enhancers, regulatory element, genome, transcriptional circuits, chromatin, histone, ChIP-seq, development, ganglionic eminence, GABA neuron, basal ganglia, telencephalon
