Chromatin Environment and Cellular Context Specify Compensatory Activity of Paralogous MEF2 Transcription Factors

摘要

Compensation among paralogous transcription factors(TFs) confers genetic robustness of cellular processes,but how TFs dynamically respond to paralogdepletion on a genome-wide scale in vivo remainsincompletely understood. Using single and doubleconditional knockout of myocyte enhancer factor 2(MEF2) family TFs in granule neurons of the mousecerebellum, we find that MEF2A and MEF2D playfunctionally redundant roles in cerebellar-dependentmotor learning. Although both TFs are highly expressedin granule neurons, transcriptomic analysesshow MEF2D is the predominant genomic regulatorof gene expression in vivo. Strikingly, genome-wideoccupancy analyses reveal upon depletion ofMEF2D, MEF2A occupancy robustly increases at asubset of sites normally bound to MEF2D. Importantly,sites experiencing compensatory MEF2Aoccupancy are concentrated within open chromatinand undergo functional compensation for genomicactivation and gene expression. Finally, motor activityinduces a switch from non-compensatory tocompensatory MEF2-dependent gene regulation.These studies uncover genome-wide functionalinterdependency between paralogous TFs in thebrain.