Transcriptomic and Metabolomic Analysis Reveals Multifaceted Impact of Gcn5 Knockdown in Drosophila Development

<b>Background:</b> General control nonderepressible 5 (Gcn5) is a lysine acetyltransferase (KAT) that is evolutionarily conserved across eukaryotes, with two homologs (Kat2a and Kat2b) identified in humans and one (Gcn5) in <i>Drosophila</i>. Gcn5 contains a P300/CBP-associated factor (PCAF) domain, a Gcn5-N-acetyltransferase (GNAT) domain, and a Bromodomain, allowing it to regulate gene expression through the acetylation of both histone and non-histone proteins. In <i>Drosophila</i>, Gcn5 is crucial for embryonic development, with maternal Gcn5 supporting early development. However, the functional mechanisms of Gcn5 after the depletion of maternal deposits remain unclear. <b>Methods:</b> Our study employed the Gal4/UAS-RNAi system to achieve whole-body or heart-specific <i>Gcn5</i> knockdown in <i>Drosophila</i> and selected 96-hour-old surviving larvae for transcriptomic and metabolomic analyses. <b>Results:</b> Omics results revealed that Gcn5 knockdown significantly impacts various metabolic pathways, as well as lysosomes, non-homologous end-joining, Toll and Imd signaling pathways, and circadian rhythms, among others. Furthermore, defects in chitin synthesis may be associated with impaired pupation. Additionally, heart-specific <i>Gcn5</i> knockdown affected cardiac physiology but appeared to have a potential protective effect against age-related cardiac decline. <b>Conclusions:</b> These findings deepen our understanding of Gcn5's roles in <i>Drosophila</i> development and provide valuable insights for developing Gcn5-targeted therapies, particularly considering its involvement in various human diseases.