Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation

Chemical modifications on histones, DNA, and RNA robustly impact gene regulation. Installation of the RNA modification m6A leads to altered mRNA stability and translation. Emerging data suggest that perturbations in m6A feedback on epigenetic checkpoints and vice versa.RNA methylation of intracisternal A particle, a type of repetitive element, is required for proper heterochromatin formation and maintain genome integrity.Loss of m6A in mouse embryonic stem cells enhances the stability of chromatin-associated RNAs, leading to more-open chromatin and active transcription.m6A destabilizes transcripts that encode histone-modifying enzymes and complexes, including KDM6B, CBP, and P300.The histone elongation mark H3K36me3 guides m6A deposition.Xist-mediated silencing of the X chromosome requires m6A deposition and recognition by reader proteins.m6A influence extends beyond mRNA stability, and investigation of functional effects of m6A on RNA biogenesis should be considered in physiological and mechanistic studies. 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. 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.