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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018477-44
Application #
9857009
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Silva, Corinne M
Project Start
1998-10-01
Project End
2021-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
44
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
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