Metabolic sinkholes: Histones as methyl repositories

Abstract

Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.

Fig 1. Histones as sinks for methyl groups and their interplay with other methyl sinks.

In the methionine cycle, SAM conversion to SAH is contingent on the presence of methyl acceptors, often referred to as methyl sinks. SAH can be further metabolized through the transsulfuration pathway, contributing to the synthesis of essential sulfur-containing molecules such as cysteine and glutathione. Cells can methylate various substrates to serve as methyl sinks. Among these reactions, an inverse relationship exists between HMTs and NNMT, which generates 1MNA, in cancer cells, as well as between HMTs and PEMT, which generates PC, in normal cells. This suggests that histone methylation by HMTs can be employed as an alternative strategy to maintain an appropriate SAM/SAH ratio when NNMT or PEMT activities are low in cancer and normal cells, respectively. The choice of which pathway to utilize may be influenced by factors including the capacity and limitations of each methyl sink, the downstream functions of the methylated reaction products, the fate of the methyl group itself, and the subsequent metabolism of SAH. Importantly, changes in histone methylation in response to methyl sink usage do not appear to correlate with alterations in the expression of genes typically associated with histone methylation. THF–tetrahydrofolate; R and R’ = fatty acids.