H3K9me3-based gene silencing and cellular identity

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The overarching goal of the research in the Salz lab is to understand the regulatory logic and molecular mechanisms underlying cell fate choice and commitment. As loss of cell fate leads to developmental disorders, cancer, and infertility, a comprehensive understanding of the many different mechanisms used by cells to establish and secure their chosen fate is essential. Our current work is focused on the female/male fate choice in the Drosophila germline, where we have found that female germ cell identity depends on the permanent repression of testes genes. This proposal builds on our exciting, published work showing that discrete gene- specific blocks of repressive H3K9me3 chromatin silences key regulatory genes normally expressed in the male germline. The repressive H3K9me3 histone modification is best known for its role in constitutive heterochromatin formation and the repression of transposable elements, but recent work in organisms ranging from fission yeast to humans (including our own) reveals that H3K9me3 peaks are also associated with the silencing of protein- coding genes normally expressed in other tissues. Although these emerging studies identify H3K9me3-mediated gene silencing as a conserved and vital strategy for securing cell fate, there is very little information about how H3K9me3 is recruited to protein-coding genes. And there is no information about whether the mechanism governing H3K9me3-mediated gene silencing in one tissue is generalizable to other tissues. These gaps limit our understanding of H3K9me3's role in silencing lineage inappropriate genes in normal development and may therefore impinge on our ability to diagnose and treat disease. The research proposed in this MIRA application will build on our foundational work in the Drosophila germline to fill these gaps in knowledge. Using the powerful genetic approaches and exciting modern technologies available in the fly, we expect our work in female germ cells to accelerate the discovery of new genes and molecular mechanisms relevant to H3K9me3-medidated gene silencing. Our new studies in the larval brain will extend these findings by determining whether somatic cells use an analogous silencing mechanism. When complete, these studies will provide fundamental insights into one of the least understood epigenetic mechanisms governing cell fate choice and commitment.