(A) Analysis showing rank percentile position of total HMTs among correlations of NNMT expression to 56,200 genes and vice versa in 48 distinct healthy tissue types from the GTEx project. Bubble size is inversely proportional to the log of the “relative reciprocal score,” the sum of squares of the ranks of total HMTs/NNMT in the reciprocal distribution (see Methods). The dashed grey box indicates correlations in the strongest 2.5% of anticorrelated genes, with tissues labelled. (B) Volcano plot showing Spearman’s correlation and FDR for expression of NNMT vs. 56,200 genes in a pan-cancer analysis of GTEx primary tumours across 48 tissue types. HMT-encoding genes are shown as points coloured according to association with transcriptional regulation; correlation for total HMT expression is shown as a black point. (C) Analysis showing rank percentile position of total HMTs among correlations of PEMT expression and vice versa in healthy tissue types from the GTEx project. Bubble size and dashed grey box as in panel 2A. (D) Volcano plot showing Spearman’s correlation and FDR for expression of PEMT vs. 56,200 genes in a cross-tissue analysis of 18 tissue types with a strong HMT-PEMT relationship (within the grey box in panel 2C). HMT-encoding genes are shown as points as in panel 2B. (E) Violin plot showing Spearman’s correlation to PEMT of HMTs (black, right) or other genes (left, grey) in 375 patient samples from the gastroesophageal junction. HMT-encoding genes are shown as points as in panel 2B. (F) Spearman’s correlation vs. PEMT expression of total expression of pooled HMTs added to the pool in a random order in a cross-tissue analysis of tissues with a strong HMT-PEMT relationship (within the grey box in panel 2C); 1,000 individual iterations are shown as black lines, with Loess fit trendline in red. (G) Analysis showing rank percentile position of total HMTs among correlations of PEMT expression to 60,489 genes and vice versa in 33 cancer types from the TCGA. Bubble size and dashed grey box as in panel 2A. (H) PEMT sequentially methylates phosphoethanolamine to produce PC, converting 3 molecules of SAM to SAH. (I) Analysis showing rank percentile position of HMTs classified by their substrate histone lysine residues among correlations of NNMT expression and vice versa in cancer types from the TCGA. Bubble size and dashed grey box as in panel 2A. (J) Analysis showing rank percentile position of HMT sets methylating distinct histone lysine residues among correlations of PEMT expression to 56,200 genes and vice versa in a pan-tissue analysis of 18 tissue types from the GTEx with a strong HMT-PEMT relationship (within the grey box in panel 2C). Bubble size and dashed grey box as in panel 2A. (K) Analysis showing rank percentile position of HMT sets methylating distinct histone lysine residues among correlations of PEMT expression and vice versa in a pan-cancer analysis of 7 cancer types from the TCGA with a strong HMT-PEMT relationship (within the grey box in panel 2G). Bubble size and dashed grey box as in panel 2J. (L) Violin plot showing healthy tissue sample PI, a measure of proliferation inferred from sample RNA-seq gene expression data, for 48 tissue types of the GTEx arranged by the strength of the anticorrelating relationship between PEMT and total HMTs. Note the x axis is inverted as a lower relative reciprocal score indicates a stronger relationship. (M) Violin plot showing tumour PI for 31 cancer types of the TCGA arranged by the strength of the anticorrelating relationship between NNMT and total HMTs. Underlying data for all panels can be found in https://zenodo.org/record/8383542. FDR, false discovery rate; GTEx, Genotype-Tissue Expression; HMT, histone methyltransferase; NNMT, nicotinamide N-methyltransferase; PC, phosphatidylcholine; PI, proliferative index; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; TCGA, The Cancer Genome Atlas.

Peer reviewed