KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism.
Genes encoding the KDM5 family of transcriptional regulators are disrupted in individuals with intellectual disability (ID). To understand the link between KDM5 and ID, we generated five Drosophila strains harboring missense alleles analogous to those observed in patients. These alleles showed effects on neuroanatomical development, cognition, and other behaviors, in addition to a transcriptional signature that included the downregulation of many ribosomal protein genes. A similar transcriptional profile was observed in KDM5C knockout human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), suggesting a conserved role for KDM5 proteins in regulating ribosomal protein genes. Loss of ribosomal protein gene expression resulted in changes to neuronal ribosome composition. Moreover, we find that the translation efficiency of mRNAs required for mitochondrial metabolism was particularly affected upon reduction KDM5 in Drosophila neurons. Altered mitochondrial activity was confirmed through metabolomic studies that revealed decreased citric acid cycle activity. KDM5 therefore plays a key role in maintaining mitochondrial function that, when altered, could contribute to cognitive and behavioral phenotypes. Overall design: To understand how patient Claes-Jensen Syndrome (CJS) associated variants in KDM5C modeled in Drosophila affect transriptional programs in neurons, we created 5 CJS variant strains as well as a synthetic demethylase-dead strain and performed paired-end RNA-Sequencing. All variants were compared to WT KDM5. We dicovered that ribosome protein genes were downregulted acorss all ID variants. To understand how loss of KDM5 function affected translation efficiency, we performed Ribo-Seq on control and kdm5-knockdown neurons.