Impact of mutations in DNA methylation modification genes on genome-wide methylation landscapes and downstream gene activations in pan-cancer

Abstract

Background: In cancer, mutations of DNA methylation modification genes have crucial roles for epigenetic modifications genome-wide, which lead to the activation or suppression of important genes including tumor suppressor genes. Mutations on the epigenetic modifiers could affect the enzyme activity, which would result in the difference in genome-wide methylation profiles and, activation of downstream genes. Therefore, we investigated the effect of mutations on DNA methylation modification genes such as DNMT1, DNMT3A, MBD1, MBD4, TET1, TET2 and TET3 through a pan-cancer analysis. Methods: First, we investigated the effect of mutations in DNA methylation modification genes on genome-wide methylation profiles. We collected 3,644 samples that have both of mRNA and methylation data from 12 major cancer types in The Cancer Genome Atlas (TCGA). The samples were divided into two groups according to the mutational signature. Differentially methylated regions (DMR) that overlapped with the promoter region were selected using minfi and differentially expressed genes (DEG) were identified using EBSeq. By integrating the DMR and DEG results, we constructed a comprehensive DNA methylome profiles on a pan-cancer scale. Second, we investigated the effect of DNA methylations in the promoter regions on downstream genes by comparing the two groups of samples in 11 cancer types. To investigate the effects of promoter methylation on downstream gene activations, we performed clustering analysis of DEGs. Among the DEGs, we selected highly correlated gene set that had differentially methylated promoter regions using graph based sub-network clustering methods. Results: We chose an up-regulated DEGs cluster where had hypomethylated promoter in acute myeloid leukemia (LAML) and another down-regulated DEGs cluster where had hypermethylated promoter in colon adenocarcinoma (COAD). To rule out effects of gene regulation by transcription factor (TF), if differentially expressed TFs bound to the promoter of DEGs, that DEGs did not included to the gene set that effected by DNA methylation modifiers.

Epigenetic Regulation of Genomic Stability by Vitamin C

“…Unopposed DNA methyltransferase activity due to loss of TET function can cause DNA hypermethylation, and decreased TET1-3 expression or reduced 5hmC levels in the genome are common across multiple solid tumors (Haffner et al, 2011;Kudo et al, 2012;Yang et al, 2013Yang et al, , 2015 and blood cell malignancies (Ko et al, 2010;Lemonnier et al, 2018;Zhang et al, 2018). Similar to the lineage bias observed for mutation of DNMTs, TET1 and TET3 are more frequently mutated in carcinomas Lee et al, 2020), whereas TET2 deletions and missense mutations induce loss of its catalytic function and are observed at much higher frequency, in ∼10-30% of patients with either clonal hematopoiesis ( (Busque et al, 2012;Jaiswal et al, 2014;Bowman et al, 2018), myeloid (Abdel-Wahab et al, 2009;Delhommeau et al, 2009;Langemeijer et al, 2009), or lymphoid (Quivoron et al, 2011;Lemonnier et al, 2012) malignancies.…”

Demethylation of Nucleobases and Current Developments

“…TET1 ve TET3'deki mutasyonlar hematopoietik malignitelerde daha az sıklıkla görülmektedir. Son zamanlarda TET3 defektinin insanlarda mental retardasyona neden olduğu böylece bir DNA demetilasyon geninin Mendel hastalığı ile ilişkilendirildiği görülmüştür 43 .…”

Crosstalk Between DNA Methylation and Gene Mutations in Colorectal Cancer

“…CIMP, reported in 20–30% of sporadic CRCs ( 7 ), is characterized by hyper-methylation of CpG islands located in promoters that regulate the activity of several tumor suppressor genes and other CRC related genes. It is well known that specific mutations can modify DNA methylation ( 8 ) and that DNA methylation changes can cause an increase in mutation rate ( 9 ). In CRC, 10–40% lower levels of absolute methylation than normal colon tissue within the whole genome have been determined ( 10 ).…”