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.
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.
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