Histone methyltransferase activity affects metabolism in human cells independently of transcriptional regulation

• Published in: PLoS biology Vol. 21; no. 10; p. e3002354
• Main Authors: Perez, Marcos Francisco, Sarkies, Peter
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 26.10.2023; Public Library of Science (PLoS)
• Subjects: Biology and life sciences; Breast cancer; Cancer; Cell metabolism; Cellular control mechanisms; Chromatin; Enzymes; Gene regulation; Genes; Genetic aspects; Genetic transcription; Genomes; Histone methyltransferase; Histones; Homocysteine; Mass spectrometry; Medicine and Health Sciences; Metabolism; Metabolites; Metabolomics; Methionine; Methylation; Methyltransferases; Physical Sciences; Physiological aspects; Proteins; Proteomics; Retinoblastoma; S-Adenosylmethionine; Scientific imaging; Short Reports; Standard scores; Transcription; Tumor cell lines; Tumor suppressor genes; Tumors; Spain
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002354

The N-terminal tails of eukaryotic histones are frequently posttranslationally modified. The role of these modifications in transcriptional regulation is well-documented. However, the extent to which the enzymatic processes of histone posttranslational modification might affect metabolic regulation is less clear. Here, we investigated how histone methylation might affect metabolism using metabolomics, proteomics, and RNA-seq data from cancer cell lines, primary tumour samples and healthy tissue samples. In cancer, the expression of histone methyltransferases (HMTs) was inversely correlated to the activity of NNMT, an enzyme previously characterised as a methyl sink that disposes of excess methyl groups carried by the universal methyl donor S-adenosyl methionine (SAM or AdoMet). In healthy tissues, histone methylation was inversely correlated to the levels of an alternative methyl sink, PEMT. These associations affected the levels of multiple histone marks on chromatin genome-wide but had no detectable impact on transcriptional regulation. We show that HMTs with a variety of different associations to transcription are co-regulated by the Retinoblastoma (Rb) tumour suppressor in human cells. Rb-mutant cancers show increased total HMT activity and down-regulation of NNMT. Together, our results suggest that the total activity of HMTs affects SAM metabolism, independent of transcriptional regulation.