Abstract
Mono-methylation of the fourth lysine on the N-terminal tail of histone H3 was found to support the induction of RNA polymerase II transcription in S. cerevisiae during nutrient stress. In S. cerevisiae, the mono-, di- and tri-methylation of lysine 4 on histone H3 (H3K4) is catalyzed by the protein methyltransferase, Set1. The three distinct methyl marks on H3K4 act in discrete ways to regulate transcription. Nucleosomes enriched with tri-methylated H3K4 are usually associated with active transcription whereas di-methylated H3K4 is associated with gene repression. Mono-methylated H3K4 has been shown to repress gene expression in S. cerevisiae and is detected at enhancers and promoters in eukaryotes. S. cerevisiae set1Δ mutants unable to methylate H3K4 exhibit growth defects during histidine starvation. The growth defects are rescued by either a wild-type allele of SET1 or partial-function alleles of set1, including a mutant that predominantly generates H3K4me1 and not H3K4me3. Rescue of the growth defect is associated with induction of the HIS3 gene. Growth defects observed when set1Δ cultures were starved for isoleucine and valine were also rescued by wild-type SET1 or partial-function set1 alleles. The results show that H3K4me1, in the absence of H3K4me3, supports transcription of the HIS3 gene and expression of one or more of the genes required for biosynthesis of isoleucine and valine during nutrient stress. Set1-like methyltransferases are evolutionarily conserved, and research has linked their functions to developmental gene regulation and several cancers in higher eukaryotes. Identification of mechanisms of H3K4me1-mediated activation of transcription in budding yeast will provide insight into gene regulation in all eukaryotes.
Highlights
Set1 is the sole H3K4 histone methyltransferase (HMTase) in S. cerevisiae that catalyzes the mono, di- and tri-methylation of the fourth lysine on the amino terminal tail of histone H3 (Briggs et al 2001; Qu et al 2018; Shilatifard 2012)
Studies in S. cerevisiae have shown that H3K4me1 inhibits RSC-independent chromatin remodeling thereby preventing the induction of osmostress genes (Nadal-Ribelles et al 2015)
In contrast to these repressive roles, the work here using partial-function variants of the HMTase Set1 shows that H3K4me1 supports activation of Pol II transcription when S. cerevisiae is subjected to nutrient starvation
Summary
Set is the sole H3K4 histone methyltransferase (HMTase) in S. cerevisiae that catalyzes the mono-, di- and tri-methylation of the fourth lysine on the amino terminal tail of histone H3 (Briggs et al 2001; Qu et al 2018; Shilatifard 2012). The SET family of H3K4 histone methyltransferases is conserved in eukaryotes (Miller et al 2001; Takahashi et al 2011). Mutations in Set1-like H3K4 HMTases alter segmentation in Drosophila melanogaster and floral development in Arabidopsis thaliana (Breen 1999; Jiang et al 2011; Shilatifard 2012). Human homologs of Set, including MLL1 and its translocation alleles, are implicated in hematological malignancies, such as mixed lineage leukemia, acute myeloid. The importance of Set family proteins in biological processes from yeast to humans underscores their importance in gene regulation (Cenik and Shilatifard 2021)
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