Genetic and epigenetic mechanisms of developmental gene regulation

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Project Summary/Abstract My lab is broadly focused on developmental gene regulation. We study the transcriptional mechanisms that control determination and maintenance of cell fates over time. In particular, we seek to understand how access to regulatory DNA is spatiotemporally controlled. Because many developmental disorders and diseases acquired later in life are a consequence of gene regulatory defects, a better understanding of the underlying mechanisms is crucial for preventing diseases and improving their outcomes. We combine genomic, genetic and biochemical approaches in Drosophila melanogaster. The fly system offers multiple strengths, including a powerful ability to manipulate gene activity with temporal and spatial precision, small genome size, which affords cheap genomics, and a deep knowledge of the relevant genetic pathways, nearly all of which are conserved in humans. Research during the term of this grant will explore multiple questions at the core of modern developmental biology and the field of epigenetic gene regulation. We will investigate how the transcriptional programs underlying tissue identity are deployed in the proper temporal sequence during development. We have uncovered a temporal cascade of transcription factors which we hypothesize control the sequential activation and inactivation of transcriptional enhancers over time. We have termed these transcription factors as “chromatin gatekeepers” due to their requirement for opening and closing access to DNA regulatory elements. The mechanisms by which enhancers are inactivated, or “decommissioned” over time are particularly understudied. One of our objectives is to decipher these mechanisms. We will also investigate how information about decisions made earlier in development is propagated over time. A key to unlocking this question is a unique genetic resource we recently generated that enables us to directly test the function of histones. Histones are subject to a diverse array of post-translational modifications (PTMs) that are thought to serve as carriers of epigenetic information to regulate many DNA-templated processes. However, evidence supporting a functional role of histone PTMs in animals is largely correlative due to the difficulty in creating mutant histone genotypes in animals. Drosophila is distinct amongst animal models in that the histone genes reside at a single locus in the genome. We can replace the endogenous histone genes with tailor-made versions, thereby providing us with the first opportunity to distinguish between regulatory information that is directly encoded in the DNA sequence, and information that is epigenetically propagated. We will employ this approach to interrogate the molecular role that histone PTMs play in enhancer regulation and in heritable control of gene expression. MIRA funding would unify our research topics into a single funding mechanism. This will enable me to spend more time at the bench mentoring students, collaborating with other scientists, and exploring new and unexpected areas of research. Thus, MIRA support would maximize our ability to contribute to a mechanistic understanding of gene regulation, and the in the longer term, to leverage this insight toward understanding of disease etiology and treatment.