A Role for Set1/MLL-Related Components in Epigenetic Regulation of the Caenorhabditis elegans Germ Line

Abstract

The methylation of lysine 4 of Histone H3 (H3K4me) is an important component of epigenetic regulation. H3K4 methylation is a consequence of transcriptional activity, but also has been shown to contribute to “epigenetic memory”; i.e., it can provide a heritable landmark of previous transcriptional activity that may help promote or maintain such activity in subsequent cell descendants or lineages. A number of multi-protein complexes that control the addition of H3K4me have been described in several organisms. These Set1/MLL or COMPASS complexes often share a common subset of conserved proteins, with other components potentially contributing to tissue-specific or developmental regulation of the methyltransferase activity. Here we show that the normal maintenance of H3K4 di- and tri-methylation in the germ line of Caenorhabditis elegans is dependent on homologs of the Set1/MLL complex components WDR-5.1 and RBBP-5. Different methylation states that are each dependent on wdr-5.1 and rbbp-5 require different methyltransferases. In addition, different subsets of conserved Set1/MLL-like complex components appear to be required for H3K4 methylation in germ cells and somatic lineages at different developmental stages. In adult germ cells, mutations in wdr-5.1 or rbbp-5 dramatically affect both germ line stem cell (GSC) population size and proper germ cell development. RNAi knockdown of RNA Polymerase II does not significantly affect the wdr-5.1–dependent maintenance of H3K4 methylation in either early embryos or adult GSCs, suggesting that the mechanism is not obligately coupled to transcription in these cells. A separate, wdr-5.1–independent mode of H3K4 methylation correlates more directly with transcription in the adult germ line and in embryos. Our results indicate that H3K4 methylation in the germline is regulated by a combination of Set1/MLL component-dependent and -independent modes of epigenetic establishment and maintenance.

Author Summary

The germ line transmits both genetic and epigenetic information between and across generations. The germ line uniquely retains developmental totipotency, and this property of germ cells is likely embedded in epigenetic information that is retained throughout the germ line cycle, within and across each generation. The methylation of Histone H3 on Lysine 4 (H3K4me) has been identified as both a mark of active transcription and a potential component of “epigenetic memory.” We show that C. elegans homologs of components of a conserved H3K4 methyltransferase complex, the Set1/MLL complex, are important for normal H3K4 methylation in C. elegans germ cells and early embryos. Interestingly, Set1/MLL component dependent H3K4 methylation can occur independently of transcription in early embryonic germline and somatic blastomeres, and also in adult germline stem cells. A separate H3K4 methylation mechanism that operates independently of Set1/MLL component activities appears more dependent on ongoing transcription. We hypothesize that H3K4 methylation is maintained throughout the germ cell cycle by alternating transcription-dependent and -independent mechanisms that maintain this component of the germline epigenome.