Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation

Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications that powerfully impact transcript turnover and translation adds another layer of dynamic gene regulation. Central to precise and synchronized regulation of gene expression is intricate crosstalk between multiple checkpoints involved in transcript biosynthesis and processing. There are more than 100 internal modifications of RNA in mammalian cells. The most common is N⁶-methyladenosine (m⁶A) methylation. Although m⁶A is established to influence RNA stability dynamics and translation efficiency, rapidly accumulating evidence shows significant crosstalk between RNA methylation and histone/DNA epigenetic mechanisms. These interactions specify transcriptional outputs, translation, recruitment of chromatin modifiers, as well as the deployment of the m⁶A methyltransferase complex (MTC) at target sites. In this review, we dissect m⁶A-orchestrated feedback circuits that regulate histone modifications and the activity of regulatory RNAs, such as long noncoding (lnc)RNA and chromosome-associated regulatory RNA. Collectively, this body of evidence suggests that m⁶A acts as a versatile checkpoint that can couple different layers of gene regulation with one another.