A not yet fully characterized multicomponent complex catalyzes the formation of m6A in mammals. The two methylases methyltransferase-like 3 (Mettl3, also known as MT-A70) and methyltransferase-like 14 (Mettl14) form the core of the complex and associate with additional regulatory factors such as WTAP (Wilm’s tumour 1 associating protein) (Figure 1c) [52 and 57]. The precise biological functions of m6A-methyltransferases are not fully understood but emerging evidence implicates a role in embryo development, gametogenesis and stem cell self-renewal. Mouse ES cells lacking Mettl3 and Mettl14 lost self-renewal

capability and the decreased levels of m6A in mRNAs of developmental regulators correlated with binding of the mRNA stabilizer HUR, indicating selleckchem Pirfenidone purchase that m6A methylation inversely correlated with mRNA stability and is needed to maintain pluripotency [52]. During embryo development expression Mettl3 is temporarily controlled, and inactivation of the plant homolog leads to cell division defects and embryo development failure [58]. In adult flies, Mettl3 expression is highest in reproductive organs

and regulates gametogenesis [59]. Similar to DNA m5C-methylation, also RNA m6A-methylation can be reverted. Fat mass and obesity associated protein (Fto) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (AlkBH5) are demethylases that remove m6A from RNA (Figure 1c) [50•• and 54]. Yet, the only subtle changes in the level of m6A in RNA after Fto or AlkBH5 over-expression indicated substrate specificity

and suggests the existence of additional demethylating enzymes [54 and 60]. Genome-wide association studies linked common polymorphisms in the first intron of FTO to body mass index, risk of obesity, type 2 diabetes, polycystic ovary syndrome and cardiovascular diseases [61]. Studies in Fto loss-of-function or gain-of-function mice suggest that the main mechanism from by which Fto predisposes to obesity and metabolic syndrome is driven by obesity-prone behaviors such as increased food intake and preference for high caloric food [62 and 63]. Consistent with these studies, Fto inactivation in mice increased methylation of mRNAs encoding components of the dopamine signaling pathway and consequently the dopaminergic reward circuitry signaling was reduced [60]. Other human neurological conditions that have been linked to genetic variations in FTO include reduced brain volume, increased cognitive decline in elderly, dementia, Alzheimer’s disease, attention deficit disorder in children and depression [64].

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