The chromatin regulatory circuitry of bivalent domains

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DESCRIPTION (provided by applicant): Embryonic stem cells maintain a delicate balance between pluripotent self-renewal and directed differentiation into any fetus cell type. Precise regulation of epigenetic state, particularly at lineage-specific developmental regulators which can induce differentiation, is crucial to maintaining this poised state during early development. Remarkably, these genes are often dually marked with both activating and repressive chromatin marks, a unique chromatin structure known as a bivalent domain. Understanding the biological mechanisms governing the setup and maintenance of bivalent domains however, has remained an elusive goal despite intense interest. The proposed research will discover the chromatin regulator circuitry operating at bivalent loci using high-throughput epigenomics technologies. I will identify chromatin regulators (CR) which bind to bivalent loci by using chromatin immunoprecipitation followed by deep sequencing (ChIP-seq). I will then perturb these enzymes in mouse embryonic stem cells and measure the resulting changes in both chromatin state and gene expression. Integrating these datasets together, I will apply probabilistic graphical modeling techniques to discover functional interdependencies relating chromatin regulators, histone modifications, and transcriptional output. This study will substantially enhance our understanding of the role CRs perform in early development, and in particular, the regulatory mechanisms responsible for establishing, maintaining, and resolving bivalent domains.