Interpretation of genomic information involves integration of cellular history and extracellular environment, which ultimately occurs at the level of chromatin and is mediated by the functionally diversified cis-regulatory elements, such as enhancers, promoters, silencers and insulators. Among those, enhancers, which function as integrated transcription factor (TF) binding platforms, play a central role in directing cell type-specific gene expression. Enhancers share certain common chromatin features, such as nuclease hypersensitivity and enrichment of flanking nucleosomes for histone modifications H3K4me1 and H3K27ac. Epigenomic mapping of these simple chromatin features has revolutionized our ability to recognize enhancer elements in a genome-wide, cell type-specific and conservation independent manner. These studies revealed unexpected complexity and dynamics of enhancer utilization in different cell types. For example, key lineage-specific loci ar often characterized by the presence of simultaneously active enhancers defined by high levels of TFs, general coactivators and H3K27ac, and showing unusual sensitivity to perturbations. These clustered enhancer arrangements have been termed super-enhancers. While there is currently a considerable excitement around mammalian enhancer biology, some fundamental enhancer properties remain unexamined. For example, while a myriad of studies utilized histone modifications in enhancer mapping, there is very little insight into a functional significance of these marks at enhancer regions. In the proposed research we will use a well- defined and robust model of early cell fate decision, which we termed embryonic stem cell (ESC) to epiblast-like cell (EpiLC) transition, to study function of H3K4me1 in de novo selection of new enhancers for activation. Similarly, although super-enhancers may be critical for controlling cell fate and disease states, we do not understand how they function and whether new regulatory phenomena emerge through clustering multiple, simultaneously active enhancers. We will use the ESC to EpiLC transition model to dissect anatomy and three dimensional architecture of a dynamically regulated super-enhancer. We will address whether cross-talk between its individual elements exists, which could account for some of the unusual behaviors of super-enhancer elements. Proposed research will provide insights into basic mechanisms of pluripotency and developmental gene regulation.
Proposed research will provide wealth of new information on cell fate transitions that occur around implantation, a developmental period associated with a high rate of pregnancy loss in humans. Therefore gained knowledge will have potential clinical implications for pre- and peri-implantation diagnostics and infertility treatment. Furthermore, super-enhancer activity is an attractive target for therapy and discovery of unrecognized cancer dependencies and therefore studies of basic mechanisms underlying super-enhancer function, organization and hypersensitivity may provide critical insights facilitating these medical applications.
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