RNA methylation in gene expression regulation

Chuan He

Department of Chemistry, Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, The University of Chicago,

Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have been working on N6-methyladenosine (m6A), the most abundant messenger RNA medication in mammals. Functional studies reveal m6A methylation as a mechanism to synchronize groups of transcripts for coordinated metabolism, translation, and decay, allowing timely and coordinated protein synthesis and transcriptome switching during cell stimulation, cell differentiation, and development. Besides mRNA we found that the methyltransferases METTL3 deposits m6A modifications on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs and repeats RNAs. In mouse embryonic stem cells an m6A nuclear reader protein YTHDC1 facilitates decay of a subset of the m6A-modified carRNAs, especially LINE1 elements, through the NEXT-mediated nuclear degradation. Reducing m6A methylation by METTL3 depletion or site-specific m6A demethylation of selected carRNAs changes the levels of carRNAs and regulates the chromatin state and downstream transcription.

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