Disruption of Methionine Metabolism inDrosophila melanogasterImpacts Histone Methylation and Results in Loss of Viability

Abstract

Histone methylation levels, which are determined by the action of both histone demethylases and methyltransferases, impact multiple biological processes by affecting gene expression activity. Methionine metabolism generates the major methyl donor S-adenosylmethionine (SAM) for histone methylation. The functions of methionine metabolic enzymes in regulating biological processes as well as the interaction between the methionine pathway and histone methylation, however, are still not fully understood. Here, we report that reduced levels of some enzymes involved in methionine metabolism and histone demethylases lead to lethality as well as wing development and cell proliferation defects in Drosophila melanogaster. Additionally, disruption of methionine metabolism can directly affect histone methylation levels. Reduction of little imaginal discs (LID) histone demethylase, but not lysine-specific demethylase 2 (KDM2) demethylase, is able to counter the effects on histone methylation due to reduction of SAM synthetase (SAM-S). Taken together, these results reveal an essential role of key enzymes that control methionine metabolism and histone methylation. Additionally, these findings are an indication of a strong connection between metabolism and epigenetics.

The Transcriptional Corepressor SIN3 Directly Regulates Genes Involved in Methionine Catabolism and Affects Histone Methylation, Linking Epigenetics and Metabolism

“…2B and 5, A and B). Consistent with published work (10,(35)(36)(37), reduction of SAM-S or SET1 led to reduced global H3K4me3 levels in S2 cells (Fig. 5, C and D).…”

“…Indeed, several groups have demonstrated that histone methylation can be altered through changes in metabolism. For example, histone methylation is regulated by threonine metabolism in mouse embryonic stem cells (6), by folate metabolism in yeast and human cells (7), and by methionine metabolism in yeast, fly, mouse, and human cells (7)(8)(9)(10). Histone methylation and phosphorylation can also be modulated by changing glycolysis and serine metabolism in yeast (11).…”

Calcium‐dependent protein kinase CPK28 targets the methionine adenosyltransferases for degradation by the 26S proteasome and affects ethylene biosynthesis and lignin deposition in Arabidopsis

“…In fact, MATs function not only in ethylene biosynthesis, but also in supplying AdoMet for many methylation reactions (Kobayashi et al ., ; Ying et al ., ; Roje, ). For example, disruption of MAT activity globally impairs histone methylation, resulting in late flowering in O. sativa (Li et al ., ), slow pollen tube growth in A. thaliana (Chen et al ., ), gene array detachment in C. elegans (Towbin et al ., ), and loss of viability in Drosophila melanogaster (Liu et al ., ). Therefore, further work may be of interest to test whether histone methylation is affected in mat1/2 mutant.…”

“…First, it has been reported that MAT proteins locate not only in the cytoplasm, but also in the nucleus (Li et al ., ; Mao et al ., ; Chen et al ., ). MATs solely offer nuclear AdoMet to regulate DNA, RNA or histone methylation (Kobayashi et al ., ; Yan et al ., ; Li et al ., ; Chen et al ., ; Liu et al ., ), which may transcriptionally regulate a series of genes expression. Second, Katoh et al .…”

The MTase15 regulates reproduction in the wing‐dimorphic planthopper, Nilaparvata lugens (Hemiptera: Delphacidae)

“…), suggesting that development terminated prematurely. To confirm this observation, we examined ovary development in females with SAM synthetase ( Sam‐S ) knockdown, a gene upstream of SAMMTase in the methionine metabolic pathway (Liu et al , ). The Sam‐S functions in converting methionine to SAM, which is subsequently utilized by SAMMTase as the methyl donor for methylation.…”