KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism II.

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. To understand how loss of KDM5C affected gene expression of human iPSC induced glutamatergic neurons, created two CRISPR KO lines from L