Resultados de investigación

CCLE metabolite-proteomics correlations for HMTs and NNMT., Peer reviewed

CCLE metabolite-RNA-seq correlations for HMTs and NNMT., Peer reviewed

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., Peer reviewed

The transcriptional regulator GLYR1 may mediate NNMT down-regulation., Peer reviewed

Alteration of SAM/SAH ratio transcriptionally regulates Nnmt and HMTs., Peer reviewed

Histone methyltransferases are co-expressed and correlate with NNMT/PEMT orthologues/analogues in C. elegans., Peer reviewed

Highly expressed histone methyltransferase genes are co-expressed., Peer reviewed

NNMT expression anticorrelate globally with levels of specific histone marks genome-wide in cancer cell lines (related to Fig 3)., Peer reviewed

PEMT expression anticorrelate globally with levels of specific histone marks genome-wide in healthy tissues (related to Fig 3)., Peer reviewed

Relationship of other groups of methyltransferases to PEMT in healthy tissues., Peer reviewed