Brain development involves precise program of gene activation that establish specific neuronal phenotypes and the intricate patterns of connections between them. Understanding the molecular mechanisms underlying these selective programs of gene activation and repression that serially definite maturation of neurons represent a fundamental question in neurobiology. During the currant Grant period we have begun to characterize the functional roles of two families of novel neurally- expressed mammalian POU domain transcription factors discovered in this laboratory, providing evidence for the hypotheses that these factors are critical for the terminal differentiation of specific neuronal and glial phenotypes, and the patterns of the connections between them. We now propose to investigate the hypothesis that these POU domain factors, alone or combinatorially exert critical roles in early neural determination events, and to establish a technology permitting identification of critical target genes that subserve aspects of the developmental program directed by the POU domain factors in both the central and peripheral nervous systems. During the current Grant period we have cloned and characterized a series of novel genes that are components of co-activator and co-repressor complexes associated with nuclear receptors, and have documented that ligand binding switches the association of the co-repressor complex, containing histone deacetylase activity, with a co-activator complex containing histone acetylase activity. We hypothesize that these co-activator and co-repressor complexes also critically modulate the transcriptional actions of the POU domain factors in the nervous systems, and that different families of transcription factors recruit specific components of these complexes, modulated by distinct signal transcription pathways. Molecular biological and structural approaches will be employed to understand the molecular mechanisms underlying these regulatory events in the development of the nervous system. These investigations will provide insights into the molecular mechanisms by which two families of transcription factors control neural development and integrate, at the level of the nucleus, the diverse signal transduction pathways that are simultaneously activated in each neuron.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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Finkelstein, Robert
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Tan, Yuliang; Jin, Chunyu; Ma, Wubin et al. (2018) Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program. Mol Cell 71:526-539.e8
Belinson, H; Nakatani, J; Babineau, B A et al. (2016) Prenatal ?-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors. Mol Psychiatry 21:1417-33
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Li, Wenbo; Hu, Yiren; Oh, Soohwan et al. (2015) Condensin I and II Complexes License Full Estrogen Receptor ?-Dependent Enhancer Activation. Mol Cell 59:188-202
Wang, Jianxun; Telese, Francesca; Tan, Yuliang et al. (2015) LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat Neurosci 18:1256-64
Telese, Francesca; Ma, Qi; Perez, Patricia Montilla et al. (2015) LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation. Neuron 86:696-710
Zhang, Feng; Tanasa, Bogdan; Merkurjev, Daria et al. (2015) Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program. Proc Natl Acad Sci U S A 112:1380-5
Basnet, Harihar; Su, Xue B; Tan, Yuliang et al. (2014) Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation. Nature 516:267-71
Jin, Chunyu; Yang, Liuqing; Xie, Min et al. (2014) Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens. Proc Natl Acad Sci U S A 111:9235-40
Liu, Zhijie; Merkurjev, Daria; Yang, Feng et al. (2014) Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 159:358-73

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