University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences
University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences
University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology; University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program
University of California, Berkeley - Environmental Genomics and Systems Biology Division; Government of the United States of America - Joint Genome Institute; University of California, Berkeley - Comparative Biochemistry Program
University of California, Berkeley - Environmental Genomics and Systems Biology Division; Government of the United States of America - Joint Genome Institute; University of California - School of Natural Sciences
University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences
University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology; University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program
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.
Lindtner, Susan and Catta-Preta, Rinaldo and Tian, Hua and Su-Feher, Linda and Price, James D. and Dickel, Diane E. and Greiner, Vanille and Silberberg, Shanni N. and McKinsey, Gabriel L. and McManus, Michael T. and Pennacchio, Len A. and Visel, Axel and Nord, Alexander and Rubenstein, John L.R., Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons (April 16, 2019). Available at SSRN: https://ssrn.com/abstract=3372973 or http://dx.doi.org/10.2139/ssrn.3372973
This version of the paper has not been formally peer reviewed.
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