H3K4 Methylation in Aging and Metabolism

Abstract

During the process of aging, extensive epigenetic alterations are made in response to both exogenous and endogenous stimuli. Here, we summarize the current state of knowledge regarding one such alteration, H3K4 methylation (H3K4me), as it relates to aging in different species. We especially highlight emerging evidence that links this modification with metabolic pathways, which may provide a mechanistic link to explain its role in aging. H3K4me is a widely recognized marker of active transcription, and it appears to play an evolutionarily conserved role in determining organism longevity, though its influence is context specific and requires further clarification. Interestingly, the modulation of H3K4me dynamics may occur as a result of nutritional status, such as methionine restriction. Methionine status appears to influence H3K4me via changes in the level of S-adenosyl methionine (SAM, the universal methyl donor) or the regulation of H3K4-modifying enzyme activities. Since methionine restriction is widely known to extend lifespan, the mechanistic link between methionine metabolic flux, the sensing of methionine concentrations and H3K4me status may provide a cogent explanation for several seemingly disparate observations in aging organisms, including age-dependent H3K4me dynamics, gene expression changes, and physiological aberrations. These connections are not yet entirely understood, especially at a molecular level, and will require further elucidation. To conclude, we discuss some potential H3K4me-mediated molecular mechanisms that may link metabolic status to the aging process.

Keywords: H3K4 methylation; aging; metabolism.

Figure 1

H3K4 methylation is associated with various biological functions. H3K4me is involved in a variety of mechanisms affecting nuclear functions. The epigenetic mark is thought to promote gene transcription, and there is an increasing body of evidence showing that H3K4me is also involved in various other nuclear functions, such as origin firing, replication stress, and DNA damage responses.

Figure 2

List of histone lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for H3K4 methylation in various species. Blue lines indicate the phylogenetic relationships between H3K4 KMTs from yeast (S. cerevisiae), fruit flies (D. melanogaster) and humans (H. sapiens).

Figure 3

Histone methylation reaction and one-carbon metabolism. S-adenosylmethionine (SAM) is synthesized from ATP and methionine (Met) by methionine adenosyltransferase (MAT). Histone methyltransferases (HMTs), such as H3K4 KMTs, utilize SAM as a cofactor to transfer a methyl group to the histone substrate, yielding S-adenosylhomocysteine (SAH) and a methylated histone. In the methionine cycle, SAH is converted to homocysteine (Hcy) via S-adenosylhomocysteine hydrolase (SAHH), followed by the re-methylation of Hcy back to methionine via either methionine synthase (MS) utilizing a methyl group from 5-methyltetrahydrafolate (5-meTHF) or by betaine-homocysteine S-methyltransferase (BHMT) utilizing a methyl group from betaine. In the folate cycle, folic acid is reduced to tetrahydrofolate (THF), which can then accept a one-carbon unit from serine (Ser) or glycine (Gly), producing 5-meTHF. Threonine (Thr) is also involved in modulating SAM concentrations, as it provides both glycine and acetyl-CoA required for optimal synthesis of SAM.

Figure 4

Possible molecular mechanisms of aging-associated H3K4 methylation. A simplified illustration of H3K4me occupancy is presented. Transcription may be modulated by H3K4me3 near promoters, H3K4me2 just downstream of promoters, and promoter-distal H3K4me1. H3K4me3 is also enriched near early-firing origins, and it is involved in faithful DNA replication under both normal growth conditions and replication stress. As patterns of H3K4me change during aging, the functional roles might not only be involved in gene regulation but also in other cellular processes, such as replication stress response. Therefore, future mechanistic studies on the relationships between H3K4me and aging-related processes may provide valuable insights into the underlying mechanisms of aging.