SWING LIGAND-REGULATED ENHANCER-DEPENDENT TRANSCRIPTION

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ABSTRACT In response to estrogen-dependent gene activation, the rapid assembly of the MegaTrans complex at responsive enhancers, is suggested to assemble an RNP condensate with phase separation-like properties. The resultant condensate is required for formation of homotypic cooperative enhancer networks, and initial data suggest that these activated enhancers become rapidly associated with specific sub-nuclear bodies. Further, the enhanced transcription of enhancers located separated by many TADs by linear distance may come into closer proximity response to E2. Here, we hypothesize that by linking new mechanistic principles of ERα-bound enhancer, promoter activation events to roles of transcription at chromosomal boundaries in chromosomal architectures and relocation into specific subnuclear architectural structures, can provide mechanistic insights into the activation of large regulated enhancer programs. First, we will explore a new approach to detect single strand DNA nicking genome-wide to uncover a previously-overlooked, but required, mechanism for ligand- and signal-dependent acute activation of enhancer programs. This would uncover a component of the DNA damage program that here instead serves as required coactivators for regulated enhancer activation. We will test the hypothesis that the strongest chromosomal boundaries harbor universally-expressed genes, and that they interact both intra- and inter- chromosomally, impacting chromosomal architecture. This supports a functional association of active chromosomal boundaries with specific subnuclear architectural structures. This R03 award would permit me to generate the essential data required to establish new principles regarding dynamic enhancer activation programs and interactions with specific subnuclear architectural structures for ligand-regulated gene transcriptional programs, providing a strong experimental basis for subsequent submission of an R01 grant.