The SET-2/SET1 Histone H3K4 Methyltransferase Maintains Pluripotency in the Caenorhabditis elegans Germline

Abstract

Histone H3 Lys 4 methylation (H3K4me) is deposited by the conserved SET1/MLL methyltransferases acting in multiprotein complexes, including Ash2 and Wdr5. Although individual subunits contribute to complex activity, how they influence gene expression in specific tissues remains largely unknown. In Caenorhabditis elegans, SET-2/SET1, WDR-5.1, and ASH-2 are differentially required for germline H3K4 methylation. Using expression profiling on germlines from animals lacking set-2, ash-2, or wdr-5.1, we show that these subunits play unique as well as redundant functions in order to promote expression of germline genes and repress somatic genes. Furthermore, we show that in set-2- and wdr-5.1-deficient germlines, somatic gene misexpression is associated with conversion of germ cells into somatic cells and that nuclear RNAi acts in parallel with SET-2 and WDR-5.1 to maintain germline identity. These findings uncover a unique role for SET-2 and WDR-5.1 in preserving germline pluripotency and underline the complexity of the cellular network regulating this process.

Repression of somatic cell fate in the germline

“…In apparent contrast with the above results, we have observed a similar phenotype following inactivation of conserved subunits of the H3K4 histone methyltransferase complex SET1 (also known as COMPASS; Table 1) [115,159]. Both SET-2, the C. elegans orthologue of SET1, and the conserved WDR-5.1 subunit are responsible for global H3K4me2 and me3 in the germline, and their absence results in a temperature-sensitive Mrt phenotype peaking at generations 6-8 [74,159].…”

“…Historically, teratoma formation has been studied in mouse model systems in which their incidence is much greater [111,112]. The more recent discovery of teratomas in the C. elegans germline offers new perspectives into the molecular mechanisms regulating totipotency [113][114][115][116]. In both mouse and C. elegans, inactivation of the translational repressors has revealed important roles in maintaining germline totipotency, and in C. elegans, their absence alone is sufficient to form teratomas [113,116,117].…”

Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program

“…Notably, the sole ortholog of Set1 in C. elegans, SET-2, is required for normal germline development and fertility (Xiao et al, 2011) and soma-specific genes were ectopically upregulated in the germline of worms lacking SET-2 with loss of H3K4 methylation and germline transdifferentiation (Robert et al, 2014) again indicating a role for Set1 in repression of inappropriate germline gene expression. Similarly, removal of the Drosophila Set1, dSet1, leads to gradual GSC loss with disruption of H3K4 trimethylation in the ovary (Xuan et al, 2013).…”

“…Recently, the Set1 H3K4 methyltransferases in Drosophila and Caenorhabditis elegans (named dSet1 and SET-2, respectively) have been shown to be essential for germline stem cells (GSCs) (Xiao et al, 2011;Robert et al, 2014;Yan et al, 2014). In mouse germ cell development, conditional mutagenesis identified Mll2 as essential for both oogenesis and spermatogenesis (Glaser et al, 2009;Andreu-Vieyra et al, 2010).…”

Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline

“…Notably, other genetic perturbations have been shown to cause C. elegans germ cells to express neuronal and muscle markers, without the need for driving transcription factors. These include loss of the H3K4 methyltransferase SET-2, loss of the nuclear argonaute HRDE-1, and concomitant loss of the NuRD complex component LET-418 and the H3K4 demethylase SPR-5 (Kaser-Pebernard et al 2014;Robert et al 2014). Because these are chromatin-based factors, they are likely to have direct effects on gene transcription.…”