KDM5 proteins are highly conserved histone demethylases with several conserved domains. In addition of well-described JmJC domain, the catalytic domain, KDM5 proteins contain a JmJN domain, an ARID DNA binding domain, a C5HC2 zinc finger of unknown function and two or three histone binding PHD motifs. Whereas mammalian cells encode four KDM5 paralogs KDM5A, KDM5B, KDM5C and KDM5D, Drosophila has a single KDM5 ortholog, making of flies a good model to study the biology of KDM5 family proteins. KDM5 proteins are involved in the control of gene transcription, acting as an activator or a repressor in a context-dependent manner. Because knockout of mouse KDM5B and Drosophila kdm5 result in lethality, KDM5 proteins play an essential role in transcriptional regulation. Moreover alterations of KDM5 expression have been described in several human cancers. For example overexpression of KDM5A or KDM5B are implicated in prostate, breast and gastric cancers. However the roles of KDM5 proteins in physiological contexts and in tumor development remain poorly understood.
In order to study the biology of KDM5, our lab carried out RNA sequencing experiments of kdm5 hypomorphic mutant adult flies that have 70% less KDM5 protein than wildtype. These analyses highlighted alterations in genes required for apoptosis. Additionally anti-KDM5 ChIP sequencing experiments conducted by our lab shown that KDM5 is bound to the promoter region of several of cell death genes. Our qPCR analyses confirmed the down-regulation of many pro-apoptotic genes in kdm5 mutant flies. Moreover to verify the ChIP-seq data, we conducted ChIP qPCR experiments and confirmed the binding of KDM5 to the promoter of the Dark gene. Dark is required for the activation of Dronc initiator caspase and is essential for most of cell death. We therefore propose that kdm5 could directly participate at the induction of apoptosis.
We continue to investigate the role of KDM5 in apoptosis and to define the precise mechanism by which KDM5 controls the expression of apoptosis genes. Because KDM5 interacts with several transcription factors involved in stimulating cell death such as Myc and Foxo, these are good candidates for recruiting KDM5 to its targets. In parallel we are identifying which domains of KDM5 are required for this function. Although KDM5 is most well known for its histone demethylase activity, previous work from our lab and others have demonstrated critical KDM5 functions are independent of its well-described enzymatic activity.