The RNA N⁶-methyladenosine modification landscape of human fetal tissues

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N⁶-methyladenosine (m⁶A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m⁶A in human tissues, we generated 21 whole-transcriptome m⁶A methylomes across major fetal tissues using m⁶A sequencing. These data reveal dynamic m⁶A methylation, identify large numbers of tissue differential m⁶A modifications and indicate that m⁶A is positively correlated with gene expression homeostasis. We also report m⁶A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m⁶A. Tissue m⁶A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m⁶A modifications. Finally, we find that m⁶A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m⁶A. Our data indicate that m⁶A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m⁶A in human development and disease.