Nutritional Control of Epigenetic Processes in Yeast and Human Cells

Abstract

The vitamin folate is required for methionine homeostasis in all organisms. In addition to its role in protein synthesis, methionine is the precursor to S-adenosyl-methionine (SAM), which is used in myriad cellular methylation reactions, including all histone methylation reactions. Here, we demonstrate that folate and methionine deficiency led to reduced methylation of lysine 4 of histone H3 (H3K4) in Saccharomyces cerevisiae. The effect of nutritional deficiency on H3K79 methylation was less pronounced, but was exacerbated in S. cerevisiae carrying a hypomorphic allele of Dot1, the enzyme responsible for H3K79 methylation. This result suggested a hierarchy of epigenetic modifications in terms of their susceptibility to nutritional limitations. Folate deficiency caused changes in gene transcription that mirrored the effect of complete loss of H3K4 methylation. Histone methylation was also found to respond to nutritional deficiency in the fission yeast Schizosaccharomyces pombe and in human cells in culture. METHYLATION of histone lysine residues plays specific, highly conserved roles in various aspects of eukaryotic gene regulation and chromosome biology. For example, methylation of lysine 4 of histone H3 (H3K4) is found at sites of active transcription in fungi (Bernstein et al. 2002), plants (Zhang et al. 2009), and animals (Gu and Fire 2010), whereas H3K9 methylation is found at repressed loci in the same broad range of organisms (Nakayama et al. 2001;Jackson et al. 2002;Peters et al. 2003). Furthermore, a single lysine can accept one, two, or three methyl groups, and these three different states of histone methylation can have different functions (Fingerman et al. 2005). The yeast Saccharomyces cerevisiae has widespread histone methylation at three lysine positions on histone H3: H3K4, H3K36 (Strahl et al. 2002), and H3K79 (van Leeuwen et al. 2002). Methylations of lysines on histone H4 at H4K5, H4K8, H4K12, and H4K20 have also been reported (Edwards et al. 2011;Green et al. 2012). In S. cerevisiae, histone methyltransferase complexes are highly specific for a given lysine residue, with H3K4 methylation performed by the Set1 methyltransferase, H3K36 methylation by the Set2 methyltransferase, and H3K79 methylation by the Dot1 methyltransferase.The biochemical reaction is highly similar for these three methyltransferases-the methyl donor, S-adenosyl-methionine (SAM), is converted to S-adenosyl-homocysteine by the transfer of a single methyl group from SAM to the lysine acceptor ( Figure 1). All known histone methyltransferases and DNA methyltransferases require SAM as the methyl donor (Cheng et al. 1993;Xiao et al. 2003;Sawada et al. 2004;Jia et al. 2007). Thus, chromatin methylation marks are, in principle, susceptible to nutritional limitation.A potential source of such perturbations affecting SAM synthesis could come from nutritional deficiencies. SAM is synthesized from methionine and ATP in a reaction conserved across all domains of life (Thomas and Surdin-Kerjan 1991). Humans are dependent on di...

Histone Methyltransferase SET1 Mediates Angiotensin II–Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice

“…28,29 Here, we show that SET1 expression and SET1 binding on the endothelin-1 promoter can be upregulated in cultured endothelial cells and in the lungs in mice. More importantly, augmented expression and activity of SET1 by Ang II parallel the accumulation of H3K4Me3 on the endothelin-1 promoter and consequently endothelin-1 transactivation.…”

Undercover: gene control by metabolites and metabolic enzymes

“…In Saccharomyces cerevisiae, folate and methionine deficiency leads to reduced H3K4me2 and H3K4me3 levels (Sadhu et al 2013). Knockout of the enzymes sam1 or sam2, which are the orthologs of MAT, also diminishes H3K4me3 levels .…”

Dietary control of chromatin

“…During methylation, SAM donates its methyl group and is converted to S-adenosylhomocysteine (SAH). SAH is then hydrolyzed to homocysteine, which is converted back to methionine in a reaction that requires folate and cobalamin (i.e., vitamin B12) [41]. Consequently, histone methylation status might be influenced by fluctuations in SAM or regulators of SAM synthesis.…”

“…The idea that folate is used to regenerate methionine (hence, SAM), and sustain methylation, was recently tested in yeast [41]. Controls showed that H3K4 methylation in folate-synthesis-deficient yeast cells was rescued by exogenous folate; similarly, exogenous methionine rescued H3K4 methylation in methionine-synthesis-deficient yeast.…”

“…Controls showed that H3K4 methylation in folate-synthesis-deficient yeast cells was rescued by exogenous folate; similarly, exogenous methionine rescued H3K4 methylation in methionine-synthesis-deficient yeast. High concentrations of folate also increased SAM levels in folate-synthesis-deficient cells, and folate or methionine limitation affected methylation at one site (H3K4) more severely than another (H3K79) [41], suggesting a potential hierarchy of histone methylation responses to nutritional limitation.…”