The dynamic m(6)A methylation landscape of human tissues reveals insights into m(6)A function and regulation

Abstract

A single genome gives rise to a diversity of tissues through complex epigenomic mechanisms, including N(6)-methyladenosine (m(6)A), a widespread RNA modification that has been implicated in many critical biological processes. However, the global landscape of m(6)A in human tissues and its broad connection with human development and common diseases remain largely elusive. Using m(6)A-sequencing, we determined 21 whole-transcriptome m(6)A methylomes across major fetal tissues. These data reveal a dynamic m(6)A methylation landscape of human tissues, identify large numbers of tissue differential m(6)As, and particularly report m(6)A methylomes of long intergenic non-coding RNA (lincRNA) in human tissues, of which the lincRNAs derived from enhancers are enriched for m(6)As. Across these tissues, m(6)A is positively correlated with expression homeostasis of its host gene. Importantly, tissue m(6)A regions are often enriched for single nucleotide polymorphisms associated with expression quantitative traits and complex traits including common diseases, a number of which potentially affect m(6)A modification directly. Lastly, we find m(6)As prefer the genes with CpG-rich promoters and the promoter features regulate transcript m(6)A methylation. Together, these data provide a valuable resource and indicate m(6)A is widely regulated by human genetic variation and promoters, suggesting the broad involvement of m(6)A in human development and diseases.