Genetic And Molecular Analysis Of Mes 2 A Maternally Expressed Gene Essential For Viability Of The Germline In C Elegans PDF Download

To retain cell identity during development, cells must remember patterns of gene expression through cell division. The MES proteins in Caenorhabditis elegans are key regulators of gene expression in the germline and are necessary in parents for fertility in the next generation. MES-2, MES-3, and MES-6 form the C. elegans Polycomb Repressive Complex 2 (PRC2) and generate a repressive histone modification, methylation on Lysine 27 of Histone H3 (H3K27me), on genes repressed in the germline. MES-4 generates a different histone modification, H3K36me, on genes expressed in the germline. To further define the targets of MES protein regulation, determine if they work together to regulate gene expression, and investigate when they are important during germline development, I used genomics, genetics, and microscopy approaches. Transcript profiling of dissected mutant germlines revealed that MES-2/3/6 and MES-4 cooperate to promote expression of germline genes and repress somatic genes and genes on the X chromosome. Loss of MES-4 from germline genes causes H3K27me3 to spread to germline genes, resulting in reduced H3K27me3 elsewhere on the autosomes and especially on the X. This finding supports the model that methylation of H3K36 antagonizes methylation of H3K27 on the same histone tails. My finding that loss of MES-2, 3, or 6 results in expression from the X chromosomes and sterility, unless the X chromosome is repressed by other means, showed that the essential role of MES-2/3/6 in worms is repression of the X chromosomes in germ cells. I determined that repressive H3K27me3 is transmitted to embryos by both sperm and oocytes. By generating embryos containing some chromosomes with and some lacking H3K27me3, I showed that in embryos lacking MES-2/3/6 function, H3K27me3 is transmitted to daughter chromatids through several rounds of cell division. In embryos with MES-2/3/6 function, the mosaic pattern of H3K27me3 is perpetuated through embryogenesis. Subsequently, during germline proliferation in larval stages, H3K27me3 accumulates on all chromosomes. During germline proliferation in larvae is also when I found MES-3 to be most important for germline development in the next generation. These latter two findings suggest that germline memory is reset during germline proliferation. Taken together, my findings support a "germline memory model" in which MES-4 and H3K36me act as a memory of germline gene expression and help concentrate MES-2/3/6 repression on the X chromosome. MES-2/3/6 and H3K27me3 act as a memory of germline gene repression, most importantly on the X chromosomes. The germline memory generated by the MES proteins is epigenetically transmitted across generations and is critical for the proper development of nascent germ cells.