Counteracting H3K4 methylation modulators Set1 and Jhd2 co-regulate chromatin dynamics and gene transcription

Abstract

Histone H3K4 methylation is connected to gene transcription from yeast to humans, but its mechanistic roles in transcription and chromatin dynamics remain poorly understood. We investigated the functions for Set1 and Jhd2, the sole H3K4 methyltransferase and H3K4 demethylase, respectively, in S. cerevisiae. Here, we show that Set1 and Jhd2 predominantly co-regulate genome-wide transcription. We find combined activities of Set1 and Jhd2 via H3K4 methylation contribute to positive or negative transcriptional regulation. Providing mechanistic insights, our data reveal that Set1 and Jhd2 together control nucleosomal turnover and occupancy during transcriptional co-regulation. Moreover, we find a genome-wide co-regulation of chromatin structure by Set1 and Jhd2 at different groups of transcriptionally active or inactive genes and at different regions within yeast genes. Overall, our study puts forth a model wherein combined actions of Set1 and Jhd2 via modulating H3K4 methylation−demethylation together control chromatin dynamics during various facets of transcriptional regulation.

The Set1 complex is dimeric and acts with Jhd2 demethylation to convey symmetrical H3K4 trimethylation

“…This concept also provides some clarity regarding the action of Kdm5/Jarid 1 class of demethylases, which may have relevance for other classes of histone demethylases. As reported by others (Ramakrishnan et al 2016;Tu et al 2007) and again documented here, loss of Jhd2 has almost no effect in yeast grown under normal laboratory conditions. Similarly, mouse knock-out phenotypes of the Kdm5/Jarid1 genes have been difficult to interpret because they present incompletely penetrant phenotypes (Schmitz et al 2011;Scandaglia et al 2017).…”

“…Total mRNA profiles were documented to evaluate the impact of monomerizing Set1C on gene expression. Because complete removal of H3K4 methylation has only a modest effect on gene expression in yeast (Margaritis et al 2012;Howe et al 2017;Ramakrishnan et al 2016), we were not surprised to find that these dramatic alterations in the distribution and levels of H3K4 methylation also had modest effects on gene expression (Supplemental Fig. 6).…”

“…Notably, the 134 commonly affected genes whose expression increased in the three sdc1 mutant strains were enriched for ribosomal biogenesis (Supplemental Fig. 6F), which is reminiscent of the apparent role of Set1 as a repressor of ribosomal genes (Ramakrishnan et al 2016). Most of these genes are not in the 401 genes of H3K4me3 cluster 1 (105/134; 78%) or the 878 genes of H3K4me2 cluster 1 (79/134; 59%) again indicating that alterations of H3K4 methylation and expression did not correlate.…”

“…H3K4me2/3 can be removed by the Jarid1/Kdm5 class of Jumonji-domain demethylases (Liang et al 2007;Klose et al 2006;Huang et al 2010). Deletion of the only S.cerevisiae H3K4 demethylase, Jhd2, has very little effect on gene expression (Ramakrishnan et al 2016). Similarly, functional studies on the four mouse Jarid1 genes (Kdm5a-d) are confusing because ablation reveals incompletely penetrant and variegating phenotypes (Kidder et al 2014;Schmitz et al 2011;Catchpole et al 2011;Scandaglia et al 2017).…”

Study of the SAGA deubiquitination module: identification of new modulators and its implication on Spinocerebellar Ataxia Type 7

“…Western blot analyses to detect H3K4me 3 from total extracts obtained from WT, mog1Δ, set1Δ and spp1Δ strains, since Set1 and Spp1 are both components of the COMPASS complex and its deletion is linked to reduced levels of H3K4me 3 (Ramakrishnan et al, 2016;Schneider et al, 2005). As shown in Figure 24, absence of MOG1 leads to a significant decrease in .…”