KDM5 family transcriptional regulators are increasingly recognized as critical players at the interface of development and human disease. Mammalian cells encode four KDM5 paralogs (KDM5A-D), three of which are clinically significant: KDM5A or KDM5B are overexpressed in a number of cancers including breast, colorectal and melanoma, and mutations in KDM5C account for ~3% of X-linked intellectual disability patients. A lack of basic knowledge regarding the mechanisms of KDM5 action has hindered the development of therapies to treat these diseases. The long-term goal of these studies is therefore to dissect the gene- regulatory functions of KDM5 proteins using Drosophila, since the presence of a single KDM5 protein in this organism bypasses the issue of functional redundancy in mammalian cells. Previous data showed that KDM5 proteins can repress transcription via their histone demethylase activity and can activate gene expression by altering histone acetylation. In this proposal, new data demonstrate for the first time that KDM5 also influences gene expression by altering the recruitment of transcription factors to their target promoters. Specifically, KDM5 recruits the oncogenic transcription factor Myc to cell growth gene promoters, and this requires the chromatin-binding PHD motif of KDM5. KDM5 also recruits Foxo to oxidative stress resistance gene promoters, however this occurs in a PHD-independent manner. Based on these data, the first hypothesis of this proposal is that KDM5 affects transcription factor recruitment by more than one mechanism, and that this involves distinct domains of KDM5. Preliminary data also show that the expression of KDM5-Foxo co- regulated targets is reduced in a fly strain harboring an allele associated with severe intellectual disability in humans (kdm5L854F). Because the remaining 12 missense mutations in KDM5C associated with intellectual disability also occur in evolutionarily conserved residues, the second hypothesis is that the corresponding mutations in fly KDM5 will show transcriptional defects. These hypotheses will be tested by pursuing three specific aims: 1) Determine the mechanism by which KDM5 recruits Myc to cell growth genes; 2) Define the mechanism by which KDM5 recruits Foxo to oxidative stress target genes; and 3) Determine the transcriptional and phenotypic defects of kdm5 alleles analogous to human intellectual disability-associated mutations. These analyses are significant because defining how KDM5 functions in context-dependent manner will lead to new strategies for treating malignancies and cognitive phenotypes caused by dysregulation of KDM5 family proteins in humans. The proposal is innovative because it deviates from the current focus on the enzymatic function of lysine demethylase (KDM) proteins by describing two new mechanisms of gene activation by KDM5 that are independent of its enzymatic activity. An additional innovation is the analyses of kdm5 missense alleles in flies that are analogous to mutations found in patients with intellectual disability as a means to dissect the gene- regulatory functions of KDM5.
Dysregulation of members of the KDM5 family of proteins results in diverse clinical pathologies: cancer and intellectual disability. The goal of this research is to dissect the gene-regulatory activities of KDM5 using Drosophila, as the simple genetics of this model organism bypass issues of functional redundancy in mammalian cells. Based on preliminary data showing two novel functions of KDM5, analyses presented will provide a comprehensive understanding of how multi-domain transcriptional regulators affect gene expression in a context-dependent manner. Moreover, analyses presented highlight new therapeutic avenues to treat KDM5-induced malignancies and cognitive deficits.
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