MOLECULAR MECHANISMS UNDERLYING INTELLECTUAL DISABILITY CAUSED BY MUTATIONS IN THE CHROMATIN MODIFIER KDM5C

PROJECT SUMMARY/ABSTRACT – RESEARCH PROJECT Mutations in the gene encoding the transcriptional regulator lysine demethylase 5C (KDM5C) are found in patients with intellectual disability (ID). While the direct link between loss of function mutations in KDM5C and ID is clear, how KDM5C functions to mediate critical neuronal processes, and therefore the consequence of mutations for mechanisms of IDD, remains unknown. The goal of this proposal is to understand the relationship between KDM5C-regulated gene expression programs and the occurrence of ID and additional comorbid features that are observed in patients. We will achieve this by bringing together a multi-disciplinary research team with expertise in complementary analytical tools and model systems to test two hypotheses. Aim 1 tests the hypothesis that the use of human iPSC-derived in vitro cell models of KDM5C-induced ID will result in the identification of clinically relevant gene expression changes and neuronal functional deficits. One key model system we will use is iPSC-derived cerebral organoids, which recapitulate structural and molecular aspects of fetal brain development and are a critical research tool used to define the underlying cause(s) of neurodevelopmental disorders. Indeed, molecular and cellular studies using in vitro organoid systems allow us to carry out studies in a human cell context that would simply not be possible in vivo. iPSCs and organoids will be generated from two sources: (1) Cells from patients with KDM5C-induced ID from a newly recruited cohort of individuals from which we are generating a genotype-phenotype database; (2) CRISPR-Cas9-mediated gene editing to generate a KDM5C null allele and a published ID allele (KDM5CA388P) that lacks histone demethylase activity using existing iPSC lines generated from typically developing controls. We will use this system to combine morphological, functional and multi-OMICS approaches to define the impact of patient- associated mutations in KDM5C. Aim 2 tests the hypothesis that the regulation of translation efficiency in neurons by the fly homolog of KDM5C is conserved in mammalian systems and that this function is important for cognition. Here we take advantage of fly and mouse animal model systems, both as discovery tools and to test hypotheses regarding possible contributors to the cognitive effects of mutations in KDM5C. Because other inherited forms of ID have altered translation and correcting this deficit has shown promise in mouse models of other ID disorders, we will test whether altered translation similarly plays a key role in a mouse model of KDM5C-induced ID. This work is significant because we will define the etiological links between mutations in human KDM5C and ID. The proposed studies are technologically innovative in the use of complementary model systems and state-of-the-art genomics techniques such as single cell transcriptomics (scRNA-seq). It is also conceptually innovative in proposing a role for translation in KDM5C-induced ID.