Methylation of histone H3K36 in higher eukaryotes is mediated by multiple methyltransferases. Set2-related H3K36 methyltransferases are targeted to genes by association with RNA Polymerase II and are involved in preventing aberrant transcription initiation within the body of genes. The targeting and roles of the NSD family of mammalian H3K36 methyltransferases, known to be involved in human developmental disorders and oncogenesis, are not known. We used genome-wide chromatin immunoprecipitation (ChIP) to investigate the targeting and roles of the Caenorhabditis elegans NSD homolog MES-4, which is maternally provided to progeny and is required for the survival of nascent germ cells. ChIP analysis in early C. elegans embryos revealed that, consistent with immunostaining results, MES-4 binding sites are concentrated on the autosomes and the leftmost ∼2% (300 kb) of the X chromosome. MES-4 overlies the coding regions of approximately 5,000 genes, with a modest elevation in the 5′ regions of gene bodies. Although MES-4 is generally found over Pol II-bound genes, analysis of gene sets with different temporal-spatial patterns of expression revealed that Pol II association with genes is neither necessary nor sufficient to recruit MES-4. In early embryos, MES-4 associates with genes that were previously expressed in the maternal germ line, an interaction that does not require continued association of Pol II with those loci. Conversely, Pol II association with genes newly expressed in embryos does not lead to recruitment of MES-4 to those genes. These and other findings suggest that MES-4, and perhaps the related mammalian NSD proteins, provide an epigenetic function for H3K36 methylation that is novel and likely to be unrelated to ongoing transcription. We propose that MES-4 transmits the memory of gene expression in the parental germ line to offspring and that this memory role is critical for the PGCs to execute a proper germline program.
Germ cells transmit the genome from one generation to the next. The identity and immortality of germ cells are crucial for the perpetuation of species, yet the mechanisms that regulate these properties remain elusive. In C.elegans, a histone methyltransferase MES-4 is required for survival of the primordial germ cells. MES-4 methylates histone H3 at lysine 36 (H3K36), a modification previously linked to transcription elongation and involved in preventing aberrant transcription initiation within the body of genes. Surprisingly, our genome-wide analysis of MES-4 binding sites in C. elegans embryos revealed that MES-4 is capable of associating with genes that were expressed in the germ line of the parent worms but are no longer being actively transcribed in embryos. To our knowledge, this is the first example of transcription-uncoupled H3K36 methylation. We suggest that MES-4-generated H3K36 methylation serves an “epigenetic role,” by marking germline-expressed genes and by carrying the memory of gene expression from one generation of germ cells to the next.