The central objective of this research proposal is to gain novel insights into the cell biological principles underlying the regulation of gene expression in response to hormonal stimulation. My research focus is gene regulation mediated by transcriptional enhancers. Although recognized as the major organizer of gene regulation in metazoans, the precise mechanism with which enhancer complex assembled and regulate target genes in response to stimuli is still mostly not known. Preliminary data described in this proposal suggest that acutely assembled enhancers harbor ribonucleoprotein complex with a physicochemical property that is quite distinct from that of enhancers that are constitutively active. These enhancers get optimally activated once associated with inter-chromatin granules (ICGs). This proposal will link multiple experimental strategies from disciplines as diverse as molecular biology, biophysics, genomics, proteomics and microscopy to provide a comprehensive understanding of the underlying mechanism of inducible enhancer activation and chromosomal architecture. Together, this approach can significantly alter our current concepts about regulated gene transcriptional programs. Importantly, the finding and experimental skills acquired from this study will also allow the transition to an academic career as an independent investigator studying the biophysical and molecular mechanisms of ligand regulated transcriptional program using proteomic, bioinformatics and genomic approaches.

Public Health Relevance

Here, I propose a multi-disciplinary research strategy to address a fundamental, not yet answered, question in gene regulation: how genome-wide transcription is coordinated to give a precise output? My proposal is based on extensive preliminary data supporting the idea that most active hormone (Estrogen) induced enhancers recruit a phase separated ribonucleoprotein complex that behave like liquid droplets. This property allows enhancers to engage in regulatory interaction in 3D nuclear space using phase separate membraneless structures as anchors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK121871-02
Application #
9962384
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2019-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
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