All cells in multicellular eukaryotes must acquire and maintain specialized fates throughout the organism?s development and adult life. Failure to do so may result in a multitude of diseases, such as cancer and neurodegeneration. Genetically identical cells acquire different fates by launching tissue-appropriate gene expression programs. Epigenetic regulation, specifically packaging DNA into different chromatin states, offers one way for cells to activate different gene expression programs from the same genome. Chromatin regulators serve critical roles in establishing and maintaining chromatin states, as well as in epigenetic transmission of cell fate information. However, the mechanisms by which chromatin regulators control and transmit cell fate information are poorly understood. The long-term objective of my research is to elucidate how chromatin regulators establish and transmit cell fate instructions across generations and through cell divisions to guide proper development. This proposal will address this objective by determining how the chromatin regulator MES-4 transmits an epigenetic ?memory of germline? from parents to offspring, and whether the chromatin regulator MRG-1 serves as the downstream effector of MES-4 memory to specify appropriate gene expression in C. elegans primordial germ cells (PGCs). The Strome lab has shown that germline development in C. elegans relies heavily on epigenetic inheritance, offering a powerful model to study the transmission of cell fate instructions.
AIM 1 will determine how MES-4 and MRG-1 are recruited to chromatin. Our model predicts that both MES-4 and MRG-1 are recruited to the histone modification that MES-4 generates, H3K36me3. I will use biochemical techniques to test if MES-4 and MRG-1 bind directly to H3K36me3, or if they rely on binding partners for their recruitment.
AIM 2 will elucidate whether MES-4 and MRG-1 cooperate to ensure proper gene expression patterns in PGCs. I am profiling mRNAs from single pairs of sister PGCs in young larvae to identify transcriptional changes in PGCs that lack MES-4 or MRG-1. Our model predicts that PGCs that lack MES-4 or MRG-1 will show similar gene expression defects: failure to launch a germline program and aberrant mis-expression of somatic and X chromosome genes. Completion of this project will reveal how MES-4 transmits a memory of germline gene expression across generations and through cell divisions, and how this memory guides cell fate in germ cells. This contribution will increase our understanding of how normal or abnormal gene expression patterns in parents are epigenetically transmitted to influence development of their offspring. My graduate training will develop my skills as an experimentalist, computational data analyst, communicator, and educator and will prepare me to seek an academic position that combines directing a research program with teaching the next generation of scientists.
Proper development depends on genetically identical cells acquiring and maintaining different cell fates. Failure to do so can lead to tissue degeneration, cancer, sterility, and many other deleterious consequences. This proposal aims to elucidate how chromatin regulators transmit gene expression instructions from parents to offspring and through cell division, using germline development in C. elegans as a model system.
