Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5

KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to demethylase-independent gene regulatory functions that remain less characterized. To expand our understanding of the mechanisms that contribute to KDM5-mediated transcription regulation, we used TurboID proximity labeling to identify KDM5-interacting proteins. Using Drosophila melanogaster, we enriched for biotinylated proteins from KDM5-TurboID-expressing adult heads, and generated a novel control for DNA-adjacent background in the form of dCas9:TurboID. We identified both known and novel candidate proteins, including members of the SWI/SNF and NURF chromatin remodeling complexes, the non-specific lethal (NSL) complex, Mediator, and several insulator proteins. Combined, our data shed new light on potential demethylase-independent activities of KDM5. In the context of KDM5 dysregulation, these interactions may play key roles in the alteration of evolutionarily conserved transcriptional programs implicated in human disorders.