Endocrine Abstracts

Transcriptional enhancers, which function as nucleation sites for the assembly of transcription-regulating complexes across the genome, drive cell type-specific patterns of gene expression that underlie the distinct biological properties of different cell types. Although many features of active enhancers (e.g., H3K4me1, H3K27ac, enrichment of p300/CBP and Mediator, and enhancer RNA production) have been defined by genomic assays, the roles of these features in ERα enhancer function are not well understood. The Kraus lab has had a long-standing interest in enhancer biology, in particular the molecular mechanisms and kinetics of enhancer assembly in signal-regulated systems. In particular, we are interested in cell type-specific enhancers that drive biological outcomes in reproductive tissues and in hormone-dependent cancers. We have focused on enhancers formed by estrogen receptor alpha (ERα), a ligand-regulated, sequence-specific DNA-binding transcription factor that nucleates de novo enhancer formation in cells in response to estrogen signaling, as well as other transcription factors (TFs), such as Sox2, FOSL1, and PLAG1. We have used a variety of molecular, biochemical, genomic, genetic, and computational approaches to determine (1) where enhancers are formed by specific TFs across the genome, (2) the kinetics of enhancer formation and disassembly, (3) the influence of genetic variation on enhancer formation and function, and (4) the role of the specific enhancer features noted above, especially enhancer transcription, in enhancer function. In addition, we have developed new computational tools to study enhancer function, such as the Total Functional Score of Enhancer Elements (TFSEE), a robust and unbiased computational pipeline that simultaneously identifies putative subtype-specific enhancers and their cognate TFs by integrating multiple types of genomic information. Collectively, our analyses are providing new insights into enhancer complex assembly and function in a variety of biological systems.

This work is supported by grants from the U.S. National Institutes of Health (DK058110; HD087150) and the Cancer Prevention and Research Institute of Texas (RP160319, RP110471-P1) to W.L.K.

DOI: 10.1530/endoabs.54.IS3