Under this Grant, we have investigated brain-specific and hormone specific strategies of transcriptional regulation, focusing on the hypothalamic: pituitary axis, repression complexes, and the neural stem cell state. These studies have elucidated roles of the NCoR/SMRT corepressor complexes, and associated factors, including TBL1/TBLR1, HDACs and TAB2 as components of the machinery that maintain a repression checkpoint, as well as the enzymatic machinery that regulated the exchange of corepressor:coactivation complexes. Genetic approaches have elucidated the functional distinctions between NCoR and SMRT in differentiation of NSCs along a neuronal pathway, in part based on roles of SMRT in repressing the RAR-dependent induction of H3 K27 Me3 demethylation factors, revealing an additional regulatory pathway in maintaining the NSC state. By elucidating the in vivo role of the histone demethylase LSD1 and the role of methyltransferases in preventing constitutive activation by nuclear receptors. We have elucidated roles for these members of these parameters in regulation of specific gene cohorts. We have provided initial evidence of ligand-dependent interchromosomal interactions dependent on ligand- binding of nuclear receptors, and apparently requiring a motor system. These events are hypothesized to exert critical functional roles in ligand-dependent gene activation events. The central Specific Aims in this competitive renewal are to investigate the molecular mechanisms by which signals and ligands modulate long-distance, interchromosomal networks of gene interactions, and their possible actions dependent upon the presence of DNA binding site in specific classes of DNA repeats. We have developed several technologies to investigate these transcriptional strategies in a genome-wide fashion, permitting us for the first time to directly address the broad roles of DNA repeats and ncRNAs in regulated interchromosomal interactions. These will permit us to access potential roles of these events in gene regulatory programs chromosomal translocation events in tumors, signal pathways and genotoxic stress. We will investigate function connections between these signaling events by histone demethylase and roles of receptor bound enhancers in promoting interactions with interchromatin granules, linking elongation and RNA processing events to transcriptional initiation. We further propose to investigate the hypothesis that noncoding RNA transcripts and specific subclasses of DNA repeats that bind specific nuclear receptors exert roles as sensors of genetic stress and in control of nuclear architecture, using neuronal cells and neuronal stem cells as models. We suggest that these mechanisms are likely to provide important insights, and possibly new intervention strategies, into many human diseases, including neurodegeneration, defects of development, diabetes and cancer.

Public Health Relevance

Regulation by nuclear receptors including estrogen, androgen, and retinoic acid receptors play central roles in development of homeostatic programs and human disease. Recent data under this Grant has provided several paradigm-shifting insights into unexpected aspects of genome- wide regulatory strategies including control of nuclear architecture, interchromosomal interactions, and roles of non-coding RNAs and DNA repeats, which are the basis for this competitive Grant renewal proposal. Our findings will have direct implications for diseases of the endocrine system, neural development, and degenerative CNS disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034934-23
Application #
8231492
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Mamounas, Laura
Project Start
1990-08-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
23
Fiscal Year
2012
Total Cost
$460,934
Indirect Cost
$162,595
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Belinson, H; Nakatani, J; Babineau, B A et al. (2016) Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors. Mol Psychiatry 21:1417-33
Li, Wenbo; Hu, Yiren; Oh, Soohwan et al. (2015) Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation. Mol Cell 59:188-202
Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80
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
Skowronska-Krawczyk, Dorota; Ma, Qi; Schwartz, Michal et al. (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature 514:257-61
Liu, Zhijie; Merkurjev, Daria; Yang, Feng et al. (2014) Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 159:358-73
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
Basnet, Harihar; Su, Xue B; Tan, Yuliang et al. (2014) Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation. Nature 516:267-71

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