Myocyte enhancer factor‐2 and p300 interact to regulate the expression of homeostatic regulator Pumilio in Drosophila

Pumilio (Pum), an RNA‐binding protein, is a key component of neuron firing‐rate homeostasis that likely maintains stability of neural circuit activity in all animals, from flies to mammals. While Pum is ubiquitously expressed, we understand little about how synaptic excitation regulates its expression in the CNS. Here, we characterized the Drosophila dpum promoter and identified multiple myocyte enhancer factor‐2 (Mef2)‐binding elements. We cloned 12 dmef2 splice variants and used a luciferase‐based assay to monitor dpum promoter activity. While all 12 dMef2 splice variants enhance dpum promoter activity, exon 10‐containing variants induce greater transactivation. Previous work shows dPum expression increases with synaptic excitation. However, we observe no change in dmef2 transcript in larval CNS, of both sexes, exposed to the proconvulsant picrotoxin. The lack of activity dependence is indicative of additional regulation. We identified p300 as a potential candidate. We show that by binding to dMef2, p300 represses dpum transactivation. Significantly, p300 transcript is downregulated by enhanced synaptic excitation (picrotoxin) which, in turn, increases transcription of dpum through derepression of dMef2. These results advance our understanding of dpum by showing the activity‐dependent expression is regulated by an interaction between p300 and dMef2.