Cellular Systems Genetic Approaches to Understanding Regulatory Variation

Jackson Laboratory, Bar Harbor ME

Investigators

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Abstract

PROJECT SUMMARY The overarching goal of my laboratory is to determine how natural genetic variation influences chromatin biology, cell fate, and, ultimately, phenotypic diversity. Since most disease-associated variants occur in regulatory elements rather than coding genes, delineating the role of regulatory variation in normal health and disease is a critical pursuit of modern genomics. Further, when variants disrupt gene regulation early in development, it can lead to lasting defects in the structure and function of adult tissues. Regulatory element function is determined by, and can be identified through, combinatorial sets of post-translational modifications on chromatin. To understand how genetic variation impacts chromatin modification and function and results in changes in development, we exploit the rich resources in mammalian diversity by deploying a novel cellular systems genetics approach using stem cells to model cell fate and differentiation. In the past 5 years, we established this innovative platform and developed a productive program to study how genetic variability in the epigenome shapes chromatin organization, subsequent gene expression, and cell identity. Specifically, we defined extensive trans-regulation of the pluripotent genome and identified genetically determined differentiation propensity. The Baker lab is continuing to harness these collective strategies and build on these findings to address the following gaps in our knowledge: What are the molecules and mechanisms underlying regulation of the chromatin landscape? How does genetic variation influence chromatin structure and function? How does variation in the establishment of the chromatin landscape impact differentiation and development? In the current proposal, we will determine how the trans-regulation of chromatin impacts developmental disorders and answer outstanding questions in the exaptation of transposable elements. We will develop tools to screen chromatin regulators for their modification of developmental disorders and transposable element regulation. We will also determine how genetic variation impacts expanded stem cell populations that contribute to extra-embryonic tissue, improving the fidelity and reproducibility of ex vivo models of development. Together, this research program will continue to shed light on the fundamental regulatory processes that shape genome function by combining discovery-based approaches through cellular systems genetics and hypothesis-driven mechanistic studies, which will be critical to fully realize the potential of regenerative medicine.