Dissociation for living

N⁶-methyladenosine (m⁶A) is one of the most abundant RNA modifications and has an important role in many biological processes. The major writer for m⁶A is the METTL3–METTL14 complex, whereby METTL3 acts as the catalytic methyltransferase while METTL14 is thought to determine substrate specificity. However, it is unclear whether the interaction between METTL3 and METTL14 can be regulated to affect m⁶A deposition. To address this question, Huang, Zhang, Cun, Ye, Ren et al. conducted a genome-wide CRISPR–Cas9 screen and identified the acetyltransferase p300 and the kinase PAK2 as key negative regulators of the interaction between METTL3 and METTL14.

The well-known function of p300 is to catalyze acetylation of histone 3 at lysine 27 (H3K27ac) — a histone marker found in active enhancers and promoters that represents actively transcribed chromatin regions. Now, the team has shown that p300 mediates the acetylation of METTL3 specifically at H3K27ac-marked chromatin regions. Acetylation reduces the affinity of METTL3 for METTL14 bound to these regions, leading to the dissociation of METTL3 from the chromatin. As a result, m⁶A levels on RNA transcribed from these enhancer and promoters decrease. The reduced m⁶A modification increases the stability of these enhancer and promoter RNAs, which in turn promotes the expression of genes related to ferroptosis inhibition as well as tumor cell survival.