Histone methyl transferases and demethylases; can they link metabolism and transcription?

Abstract

Heritable changes to the transcriptome that are independent to changes in the genome are defined as epigenetics. DNA methylation and posttranslational modifications of histones, such as acetylation/deacetylation and methylation/demethylation of lysine residues, underlie these epigenetic phenomena, which impact on many physiological processes. This perspective focuses on the emerging biology of histone methylation and demethylation, highlighting how these reactions depend on metabolic coenzymes like S-adenosylmethionine, flavin adenine dinucleotide, and α-ketoglutarate. Furthermore, we illustrate that methyltranferases and demethylases affect many metabolic pathways. Despite the preliminary evidence that methyltranferases and demethylases could link metabolic signals to chromatin and alter transcription, further research is indispensable to consolidate these enticing observations.

Figure 1

(A) Schematic representation of post-translational modifications of histone proteins with a particular focus on histone methylation. (B) Chemical structures of SAM, FAD and α-KG. Red ring on SAM highlights the reactive sulfur atom. Arrows on FAD highlight the nitrogen atoms, which are protonized in FADH₂

Figure 2

(A) Schematic representation of how cofactor biosynthesis is dependent on intracellular energy status. The ATP produced by the intracellular metabolism of nutrients is the key molecule for the biosynthesis of cofactors. MAT converts methionine to SAM by using ATP. RFK and FLAD use also ATP to synthesize FAD from riboflavin. High intracellular ATP levels in contrast inhibit α-KGDH, a key enzyme in the TCA (tri-carboxylic-acid cycle) that converts α-ketoglutarate to succinyl-CoA (Smith et al., 1974). (B) Schematic representation of how intracellular nutrient signals are integrated to reprogram transcription. Solid arrows indicate activation of transcription, dotted lines indicate inhibition of transcription. Words depicted in blue indicate precursors for coenzymes biosynthesis; words in green indicate coenzymes directly involved in methylation (SAM) and/or demethylation (FAD and α-KG) reactions.