Decoding the Regulation and Function of RNA modifications from Epitranscriptomic and Epigenomic Data






N6-methyladenosine (m6A) is the most prevalent internal post-transcriptional modification in human transcriptome and has been shown to have important roles in various normal and pathological processes. However, the process by which m6A is deposited on mRNAs is largely unknown. Here we developed a serial of computational and experimental methods to decode the regulation of m6A methylation from epigenomic and epitranscriptomic data and demonstrated that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. Comparative analyses of ChIP-seq data for H3K36me3 and m6A-seq data revealed that majorities of m6A peaks overlapped with H3K36me3 sites and that the overlapping sites were enriched near stop codons. We also found that m6A sites identified from miCLIP are enriched in the vicinity of H3K36me3 peaks and are reduced globally when cellular H3K36me3 is depleted.  Furthermore, we show that a significant genome-wide correlation between chromatin binding of METTL14 to H3K36me3. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. The discovery of interplay between modified histones and RNA methylation represents a new regulatory layer, and an additional level of complexity, in the control of gene expression.

个人简介:杨建华,中山大学生命科学学院教授,博士生导师。2008年毕业于中山大学并获得生物化学与分子生物学博士学位。杨建华教授长期致力于开发RNA组学的方法和技术研究RNA的表观遗传调控及功能机制。近5年来,在Nature、Nature Cell Biology、European Urology、Nucleic Acids Res.和Cell Reports等杂志发表20多篇研究论文,9篇研究论文被选为ESI高引用论文,多篇研究论文被Nature Cell Biol.、Nature Reviews Genetics、Nature Chemical Biology和European Urology等杂志亮点评述,1篇论文入选“2014年中国百篇最具影响国际学术论文”。开发的计算机软件和分析平台被引用超过2500次,单篇最高他引超过900次。