Understanding the molecular logic of regulatory and epigenetic strategies that control genome-wide patterns of transcriptional response to regulatory signals, development and disease remains a key, unresolved issue. Under this Grant, we have investigated the integration of transcriptional programs by coactivators and corepressors, establishing their role in regulated gene transcription by DMA binding transcription factors, and also established the critical role of specific corepressor complex components in cofactor exchange in ligand- dependent gene activation. An unexpected role of a corepressor dependent recruitment of ubiquitylation/19S proteosome machinery in gene activation, and PARP1 as a sensor for linking specific signaling pathway to programs of transcriptional response have been discovered. Investigation of pituitary gland development as a model has permitted the in vivo characterization of these principles, and the demonstration that cell-type specification is achieved by synergistic actions of specific interacting transcription factors induced in overlapping patterns by opposing signaling gradients. In this competitive renewal, we will focus on the use of a newly-developed genome-wide location analysis method to explore the novel aspects of gene regulation and epigenetic control of transcriptional activation programs. We will explore specific epigenetic strategies of gene regulation during development and the molecular mechanisms underlying boundary element function. The hypothesis that specific gene activation programs unexpectedly require the actions of specific histone demethylases will be tested, and the underlying molecular mechanisms will be explored. Based on the discovery of the sensor function of PARP1, we will investigate the hypothesis that the basic strategy by which poly (ADP-ribose) polymerase functions in nuclear receptor-dependent gene activation involves topoisomerase-dependent DNA nicking with activation of PARP1 enzymatic action to dismiss histone H1 from a specific nucleosome. A novel aspect of LEF/TCF independent B-catenin function in cell lineage determination versus proliferation events will be explored using Pit1 gene regulation as a model. These approaches combine genomics, genetic and molecular biological approaches, providing novel insights into aspects of molecular mechanisms of regulated gene expression and organogenesis, and will provide specific insights into the molecular strategies underlying coordinated programs of gene response.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Margolis, Ronald N
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Yang, Feng; Ma, Qi; Liu, Zhijie et al. (2017) Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ER?-Regulated Transcriptional Program. Mol Cell 66:321-331.e6
Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80
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
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

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