Germ cells are responsible for the fertility and perpetuation of species and thus serve a key role in development. We are investigating the mechanisms that preserve the immortality of germ cells and guide their unique developmental program, using a combination of genetics, genomics, and molecular and biochemical approaches in the model system Caenorhabditis elegans. We previously identified four C. elegans MES proteins as being required for germ cell immortality. MES-2, MES-3, and MES-6 constitute the Polycomb Group of chromatin regulators in worms, operate as a complex, and participate in maintaining the X chromosomes in a silenced state throughout most of germline development. MES-4 binds the autosomes and may function to protect them from silencing. The MES system operates at the level of modification of histone tails in chromatin. The MES-2/3/6 complex catalyzes methylation of histone H3 Lys27, which represses gene expression. The goals of this proposal are to: a) elucidate how MES-3 and MES-6 and perhaps an alternative partner to MES-6 influence histone methylation by MES-2, b) test our prediction that MES-4 also functions to methylate histones and identify other proteins that operate with MES-4, c) investigate how MES-4 is targeted specifically to the autosomes, d) identify some of the genes whose expression is regulated by MES-2/3/6 and MES-4, and e) determine how MES- 2/3/6 and MES-4 interface with each other and with the SynMuv class of chromatin regulators. The dynamic regulation of chromatin organization is a crucial level of control of gene expression and development, and misregulation is known to contribute to disease states and cancers. Our studies will make important contributions to understanding control of chromatin states, mechanisms for discriminating between the autosomes and the sex chromosomes, and specific chromatin requirements in germ cells. ? ?
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