A fundamental question in regulatory biology is whether enhancers regulate only the coding target genes with spatial proximity, or whether they regulate chromosomal architecture, exerting transcriptional effects on genes far removed in a specific chromosome. Thus, in addition to exhibiting regulated interactions with its cognate promoter, and perhaps with other enhancers in a single TAD, it is important to solve whether signal-induced proximity of specific robustly-activated regulatory enhancers, separated by vast linear distances within a chromosome, constitute a ?first tier? network that alters the transcription of specific, interacting component enhancers. We hypothesize that this ?first tier? network, while not impacting the ability of each component enhancer to loop to and activate its cognate target coding gene promoter, nucleates formation of an architectural ?structure? that provides the machinery that licenses the robustness of the transcriptional response imparted by these individual enhancers. We will use both GRO-seq and assays of 3D architecture to test whether conceptualize a ligand-dependent distributive superenhancer connectome dictates chromosomal architecture. This would represent an entirely new perspective on enhancer networks, revealing interactions of E2-regulated enhancers that modulate whole chromosome architecture and ensemble chromosomal structures result in an unexpected integrated transcriptional response network based on actions of single, robust ?first tier? enhancers.

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An unsolved question in regulatory biology is whether enhancers dynamically regulate chromosomal architecture, exerting transcriptional effects on genes far removed in a specific chromosome. Using cell genetics approaches, the ability of a specific cohort of robust ER?-bound enhancers, separated by 11-30mb, to form a connectome in a chromosome that exerts previously unsuspected transcriptional effects on the component enhancers in this network will be investigated. This will test the hypothesis that the component enhancers of the integrated transcriptional response network exhibit an E2 regulated interaction to form an architectural structure that underlies the integrated transcriptional response, linking genomic interactions to formation of specific subnuclear architectural structures.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Silva, Corinne M
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University of California, San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
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Kim, Hong Sook; Tan, Yuliang; Ma, Wubin et al. (2018) Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells. Nature 556:510-514
Wang, Jianxun; Saijo, Kaoru; Skola, Dylan et al. (2018) Histone demethylase LSD1 regulates hematopoietic stem cells homeostasis and protects from death by endotoxic shock. Proc Natl Acad Sci U S A 115:E244-E252
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
Cardamone, Maria Dafne; Tanasa, Bogdan; Cederquist, Carly T et al. (2018) Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. Mol Cell 69:757-772.e7
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; Aggarwal, Aneel K; Rosenfeld, Michael G (2017) Physiological functions of programmed DNA breaks in signal-induced transcription. Nat Rev Mol Cell Biol 18:471-476
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

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