Coordination of germline chromatin organization mechanisms to initiate embryogenesis

About This Grant

SUMMARY The extensive epigenetic information associated with genomic DNA establishes a defined chromatin organization that instructs tissue-specific gene expression programs. Many devastating disorders, diseases, and cancers are attributed to disruption of chromatin-based regulation, yet the mechanistic underpinnings remain poorly understood, especially in vivo. Our research program leverages powerful genetic, molecular and genomic tools to investigate the causal regulatory mechanisms that govern chromatin organization and gene expression in the C. elegans germ line, an ideal system in which to address these questions. By combining technical and conceptual innovation, we have discovered many epigenetic mechanisms by which germ cells establish and balance robust activation and precise repression, at the level of individual genes and across large chromosomal domains, to ensure successful gametogenesis, fertilization, and embryogenesis. In our recent work, we used our ability to isolate germ nuclei for genomic analysis to define novel chromatin states in germ cells, identify a novel protein that links histone modifications to co-transcriptional splicing, discover a unique chromatin state that promotes the biogenesis of small noncoding piRNAs, and investigate how nucleosome remodeling in the germline promotes embryogenesis. Our current and future research is organized around investigating how germline epigenetic mechanisms anticipate and direct embryonic differentiation and development. Specifically, we will use cutting-edge, highly specific, genomic and perturbation approaches to determine how remodeling of nucleosome positioning and histone modification patterns shape the dynamic expression of germline-expressed genes, thereby coordinating maternally-provided factors to carry out successful fertilization, eggshell formation, asymmetric cell division, early blastomere identity, and onset of zygotic transcription in the embryo. Our innovative and comprehensive approaches position us to investigate these mechanisms in vivo at a scale and level of resolution not previously possible. These research directions will therefore uncover novel, fundamental mechanisms of genetic regulation and reveal causal relationships between chromatin state, gene expression and cellular function. The specific factors we focus on are highly conserved core regulators of chromatin state and gene regulation and therefore have substantial influence on gene expression in humans as well, ensuring broad applicability of our discoveries to understanding development and combating disease.