Landscape and Regulation of M ⁶A and M ⁶Am Methylome Across Human and Mouse Tissues

Abstract

N⁶-methyladenosine (m⁶A), the most abundant internal mRNA modification, and N⁶,2’-O-dimethyladenosine (m⁶Am), found at the first-transcribed nucleotide, are two examples of dynamic and reversible epitranscriptomic marks. However, the profiles and distribution patterns of m6A and m6Am across different human and mouse tissues are poorly characterized. Here we report the m⁶A and m⁶Am methylome through an extensive profiling of 42 human tissues and 16 mouse tissue samples. Globally, the m⁶A and m⁶Am peaks in non-brain tissues demonstrates mild tissue-specificity but are correlated in general, whereas the m⁶A and m⁶Am methylomes of brain tissues are clearly resolved from the non-brain tissues. Nevertheless, we identified a small subset of tissue-specific m6A peaks that can readily classify the tissue types. The number of m⁶A and m⁶Am peaks are partially correlated with the expression levels of their writers and erasers. In addition, them⁶A- and m⁶Am-containing regions are enriched for single nucleotide polymorphisms. Furthermore, cross-species analysis of m⁶A and m⁶Am methylomes revealed that species, rather than tissue types, is the primary determinant of methylation. Collectively, our study provides an in-depth resource for dissecting the landscape and regulation of the m⁶A and m⁶Am epitranscriptomic marks across mammalian tissues.