Multiple layers of gene expression regulation. Gene regulation occurs across the genome, epigenome, and epitranscriptome. Left: Beyond the DNA sequence, chromosomes are regulated by their locations, or territories, in the nucleus both relative to one another and to the nuclear lamina. Long-range interactions are further regulated by TADs within and across chromosomes. LAD, laminin-associated domain. Middle: At the epigenetic level, gene expression is regulated by reversible histone modifications within nucleosomes including methylation, acetylation, phosphorylation, ubiquitination, and sumoylation. Most DNA methylation occurs in the form of 5mC by DNA methyltransferases (DNMTs), which can be actively removed through an oxidation–DNA repair pathway involving thymine DNA glycosylase (TDG)-dependent base excision repair (BER). DNA methylation could also occur in the form of 6mA. Right: Dynamic chemical modifications on RNA regulate transcript fate through a network of RNA-specific methyltransferases (writers), demethylases (erasers), and reader proteins. Though hundreds of modifications can occur in mRNA, m6A is the most prevalent.
