Journal
NATURE GENETICS
Volume 54, Issue 9, Pages 1427-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01173-1
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Funding
- National Key R&D Program of China [2021YFA1302100]
- Program for Guangdong Introducing Innovative and Entrepreneurial Teams [2017ZT07S096]
- Natural Science Foundation of China [82072617]
- Sun Yat-sen University Intramural Funds
- Simms/Mann Family Foundation
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This study reveals that METTL3-mediated RNA N-6-methyladenosine (m(6)A) deposition leads to DNA demethylation. The m(6)A reader protein FXR1 recruits DNA 5-methylcytosine dioxygenase TET1 to chromatin, which is linked to chromatin accessibility and gene transcription.
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N-6-methyladenosine (m(6)A) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between m(6)A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA m(6)A, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA m(6)A formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA m(6)A and DNA modification in physiologic and pathogenic process. METTL3-dependent RNA N-6-methyladenosine (m(6)A) deposition can lead to DNA demethylation. The m(6)A reader FXR1 recruits DNA 5-methylcytosine dioxygenase TET1 to chromatin, which is linked to chromatin accessibility and gene transcription.
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