Epigenetic and transcriptional consequences of Intellectual Disability-associated mutations in the histone lysine demethylase KDM5.

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ABSTRACT Intellectual disabilities (ID) are a group of neurodevelopmental disorders characterized by difficulties in memory, cognition, and adaptive function by the age of 18. Whole exome sequencing from patients with ID reveals mutations in the genes encoding KDM5A, B, and C. One to three percent of X-linked ID (X-LID) is attributed to the highly neuronally expressed paralog KDM5C. KDM5 proteins are best known for their enzymatic demethylation of H3 that is tri-methylated on lysine 4 (H3K4me3), a chromatin modification associated with transcriptionally active promoters. Though Kdm5c knockout mice show cognitive phenotypes, no clinically relevant pathways have been identified and the mechanism by which KDM5 regulates transcription is still unclear. Drosophila possess a single, well conserved ortholog of KDM5 in which we can model patient- associated ID mutations to understand their effects on neuronal development. A previous study from our lab modeling ID mutations in Drosophila reveals a reduction in expression of ribosomal protein genes (RPG), total protein translation, and defects in both short and long-term memory. De novo translation is necessary for memory formation and is found to be altered in several ID disorders. Importantly, restoring translational defects are an emerging and potentially therapeutic means to improve the cognitive function of individuals with ID. Hindering the development of any therapies is a lack of understanding of how KDM5 functions molecularly to regulate the expression of RP and other genes, the extent to which this requires its canonical histone demethylase activity, and how KDM5 function is altered by ID-associated mutations. Here, we specifically address these key issues by systematically decoding the role of KDM5 in RPG expression by assessing promoter H3K4me3 levels, the KDM5 interactome, and how these are altered by ID mutations.