Nature Genetics: Lin Dongxin/Zheng Jian et al. first revealed that RNA methylation can regulate DNA methylation

The regulation of gene expression in human cells is complex and tight, but it is affected
by many factors.
Disorders in gene expression can lead to many diseases, including cancer
.
One of the most important factors affecting gene expression is epigenetic modification, such as DNA methylation modification, histone acetylation modification, etc
.

Changes in gene expression caused by DNA methylation modification changes play an important role
in the development of tumors.
For example, cancer cell genomes often have hypomethylation of oncogenes and hypermethylation of tumor suppressor genes, but the mechanism of DNA methylation changes is not fully understood
.
In addition to DNA methylation, RNA, a gene transcript, can also be modified
by methylation.

The most common RNA methylation modification known is methyladenine N6 methylation (m6A).

m6A modification of mRNA affects the stability of mRNA itself and its efficiency in translating into proteins; Recent studies have also shown that RNA-m6A modification can also inversely affect chromatin remodeling and histone modification
.

Recently, Lin Dongxin/Zheng Jian Laboratory of Sun Yat-sen University Cancer Prevention and Treatment Center, together with Professor Chen Jianjun of the Beckman Institute of Hope City National Medical Center, USA, published a research paper
titled: RNA m6A regulates transcription via DNA demethylation and chromatin accessibility in the journal Nature Genetics.

The study found that m6A modifications of RNA during transcription directly demethylated adjacent DNA, thereby increasing
chromatin accessibility and gene expression.
This study is the first to reveal that RNA methylation can regulate DNA methylation, which is of great significance
for further understanding the complex gene expression regulation mechanism.

The study first used cells cultured in vitro to conduct a series of biochemical, molecular biology and cytogenetic experiments to confirm that m6A produced by RNA at the same time as transcription can recruit the demethyltransferase TET1 through the m6A recognition protein FXR1 to demethylate adjacent DNA (Figure 1).

In order to explore the biological function of RNA m6A in regulating DNA demethylation and the relationship between abnormal regulatory mechanisms and disease, this study has been studied in depth with esophageal cancer
.

It was found that knocking out METTL3, TET1 or FXR1 gene expression could lead to changes in chromatin accessibility in the localization region, which in turn affected the transcription
of genes in the corresponding region.
They found that the RNA m6A content in esophageal cancer tissue was significantly higher than in normal tissue next to the cancer, but overall DNA methylation levels were reduced
.
DNA demethylation and high expression of genes caused by high RNA m6A are enriched in cancer-related pathways
.
Knockout of METTL3, TET1 or FXR1 can inhibit the proliferation, invasion and migration of esophageal cancer cells, and FXR1 function depends on the presence of METTL3 and TET1, which further indicates that RNA m6A negatively regulates DNA methylation in the occurrence and development of esophageal cancer
.
These findings provide new ideas
for in-depth study of the role of RNA modification in cancer.

At the same time, Nature Genetics published a review article from Shen Hongjie, a researcher from the Institute of Biomedical Sciences of Fudan University, entitled "When RNA methylation meets DNA methylation", they believe that this study reveals the important role of RNA-m6A and DNA-5mC interaction in regulating chromatin accessibility and gene transcription, which is involved in the occurrence and development of esophageal squam cell carcinoma.
It provides a new direction
for in-depth research in the field of related epiregulation.

Deng Shuang, doctoral student of Sun Yat-sen University Cancer Prevention and Treatment Center, Zhang Jialiang, distinguished associate researcher, Su Jiachun, doctoral student, and Zuo Zhixiang, researcher of Bioinformatics Platform, are the co-first authors
of this paper.
Prof.
Jian Zheng, Academician Dongxin Lin and Professor Jianjun Chen are the co-corresponding authors
of the research paper.

Since its establishment in 2015, the Laboratory of Academician Lin Dongxin of Sun Yat-sen University Cancer Prevention and Treatment Center has focused on tumor genomics and tumor epigenetics
.
The team has been recruiting postdoctoral fellows, distinguished associate researchers and researchers for a long time, and warmly welcomes talents with backgrounds in oncology, biochemistry, molecular biology and bioinformatics to join (contact: zhengjian@sysucc.
org.
cn).

Original source:

Deng， S.
， Zhang， J.
， Su， J.
et al.
RNA m6A regulates transcription via DNA demethylation and chromatin accessibility.
Nat Genet 54， 1427–1437 (2022).
https：//doi.
org/10.
1038/s41588-022-01173-1.