Histone acetyltransferases and N-terminal acetyltransferases orchestrate development and metamorphosis in the yellow fever mosquito, Aedes aegypti.

Mosquitoes, especially Aedes aegypti, transmit major human diseases such as dengue, Zika, and chikungunya. Epigenetic regulation, including histone acetylation, plays a key role in controlling Ae. aegypti development. However, the specific roles of histone acetyltransferases (HATs) and N-terminal acetyltransferases (NATs) in mosquito development remain poorly understood. In this study, we investigated 25 HAT/NAT genes functions by knocking them down via feeding Ae. aegypti larvae with dsRNA nanoformulations. Gene expression analysis confirmed that target gene expression was reduced by more than 50% in dsRNA-treated larvae. Knocking down 18 of these HATs/NATs resulted in over 50% mortality. Silencing KAT7, NATSCAN, NAT9, ATAT1, and TADA3 caused larval death, whereas knockdown of NAA80, NAA-Eco, GNPNAT1, HAT-B, and MCM3AP led to pupal mortality. Knockdown of NATSCAN, NF, TFIID, GNPNAT1, and NAA16 resulted in molting and metamorphic defects, characterized by untanned cuticles and failure to complete successful larval-pupal metamorphosis. Phylogenetic analysis of conserved domains of HATs and NATs revealed that evolutionarily conserved members cluster into distinct clades associated with larval- or pupal-specific functions. Developmental expression analysis showed stage-specific expression of these genes. Further, stage-specific expression analysis revealed that dynamic expression patterns of KAT7, RNACAT, NAT9, and NF are linked to larval growth and pupal metamorphosis. Treatment with 20-hydroxyecdysone (20E) or an ecdysone agonist increased mRNA levels of NAA30,NAA40,NAT9, and GNAT8, indicating hormonal control of histone acetylation. Ecdysone-induced HATs/NATs regulated the expression of primary ecdysone response genes: E75A and E93. These results demonstrate that HATs/NATs play key roles in Ae. aegypti development and therefore could serve as potential targets for mosquito control.