Distinct DNA methylation targets by aging and chronic inflammation: a pilot study using gastric mucosa infected with Helicobacter pylori

Satoshi Yamashita,Toshikazu Ushijima,Takao Maekita,Sohachi Nanjo,Toshiro Sugiyama,Naoko Iida,Hideyuki Takeshima,Takayuki Ando,Emil Rehnberg

doi:10.1186/s13148-019-0789-8

Satoshi Yamashita, Toshikazu Ushijima + Show 7 more

Open Access

https://doi.org/10.1186/s13148-019-0789-8

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Abstract

BackgroundAberrant DNA methylation is induced by aging and chronic inflammation in normal tissues. The induction by inflammation is widely recognized as acceleration of age-related methylation. However, few studies addressed target genomic regions and the responsible factors in a genome-wide manner. Here, we analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation.ResultsDNA methylation microarray analysis of 482,421 CpG probes, grouped into 270,249 genomic blocks, revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by inflammation, even after correction of the influence of leukocyte infiltration. A total of 61.8% of the hypermethylation was acceleration of age-related methylation while 21.6% was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae, genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones.ConclusionsMethylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa.

Highlights

Aberrant DNA methylation is deeply involved in various human disorders, including cancers [1]
Cluster analysis using the 5000 genomic blocks with the highest SD mixed up young and old gastric mucosae and past-infected (HP past) and Helicobacter pylori (HP) current gastric mucosae (Fig. 1a left). This relatively unclear separation suggested that a fraction of methylation changes by HP infection, especially in currently infected samples, was due to contamination of other types of cells, namely infiltrating leukocytes
The fractions of these three groups were separately calculated using 20 CpG sites highly methylated in respective leukocyte groups but not in gastric mucosa without HP infection (Additional file 1: Figure S1B)

Summary

Introduction

Aberrant DNA methylation is deeply involved in various human disorders, including cancers [1]. It is present in cancer tissues and in normal tissues, and its accumulation levels are associated with cancer risk in multiple types of cancers [2, 3]. Target genes for methylation induction in normal tissues by aging and chronic inflammation are still elusive, mainly due to low DNA methylation levels, even if induced. We analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation

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