Histone deacetylases synergistically regulate juvenile hormone signaling in the yellow fever mosquito, Aedes aegypti

Controlling Aedes aegypti mosquitoes is crucial for managing mosquito-transmitted diseases like dengue, zika, chikungunya, and yellow fever. One of the efficient methods to control mosquitoes is to block their progression from the larval to the adult stage. Juvenile hormones (JH) maintain the larval stage and ensure proper developmental timing for transitioning from larval-pupal-adult stages. Our previous studies showed that histone deacetylases (HDACs) regulate JH signaling and metamorphosis in the red flour beetle Tribolium castaneum. However, the role of HDACs in regulating JH signaling in Ae. aegypti mosquito is unknown. To investigate the role of HDACs in JH signaling, we knockdown each HDAC coding gene in Aag-2 cells derived from Ae. aegypti. Knockdown of HDAC1, HDAC4, and HDAC11 increased the expression of the JH primary response gene, Kr & uuml;ppel homolog 1 (Kr-h1), which represses the larval-pupal metamorphosis. Moreover, the simultaneous knockdown of these three HDACs synergistically increased the Kr-h1 promoter activity and its expression, mimicking JH action in inducing Kr-h1. Nevertheless, each HDAC regulates the transcription of different sets of genes, except for a few common genes involved in JH signaling. Furthermore, the knockdown of these HDACs in Ae. aegypti larvae caused different phenotypes apart from delayed pupation: HDAC1 knockdown caused larval growth retardation, body shrinkage, and eventual death; HDAC4 knockdown led to incomplete head capsule shedding after metamorphosis; and HDAC11 knockdown caused higher pupal mortality. Our data demonstrates functional overlap and distinct functions for HDAC1, HDAC4, and HDAC11 in modulating JH signaling, with each HDAC having a unique role in mosquito development.