KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability in Drosophila

The precise coordination of gene expression is critical for developmental programs, and histone modifying proteins play important, conserved roles in fine-tuning transcription for these processes. One such family of proteins are KDM5 enzymes that interact with chromatin through demethylating H3K4me3 as well as demethylase-independent mechanisms that remain less understood. The single kdm5 ortholog in Drosophila is an essential gene that has crucial developmental roles in a neuroendocrine tissue, the prothoracic gland. To characterize the regulatory functions of KDM5, we examined its role in coordinating gene expression programs critical to cellular homeostasis and organismal viability in larval prothoracic gland cells. Utilizing targeted genetic experiments, we analyzed the relationship between critical cell signaling pathways, particularly MAPK, and the lethality caused by loss of kdm5. Integrating KDM5 genome binding and transcriptomic data revealed conserved and tissue-specific transcriptional programs regulated by KDM5. These experiments highlighted a role for KDM5 in regulating the expression of a set of genes critical for the function and maintenance of mitochondria. This gene expression program is key to the essential functions of KDM5, as expression of the mitochondrial biogenesis transcription factor Ets97D/Delg, the Drosophila homolog of GABP, in prothoracic gland cells suppressed the lethality of kdm5 null animals. Consistent with this, we observed morphological changes to mitochondria in the prothoracic gland of kdm5 null mutant animals. Together, these data establish KDM5-mediated cellular functions that are both important for normal development and could also contribute to KDM5-linked disorders when dysregulated.