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

SUMMARY

Compensation among paralogous transcription factors (TFs) confers genetic robustness of cellular processes, but how TFs dynamically respond to paralog depletion on a genome-wide scale in vivo remains incompletely understood. Using single and double conditional knockout of myocyte enhancer factor 2 (MEF2) family TFs in granule neurons of the mouse cerebellum, we find that MEF2A and MEF2D play functionally redundant roles in cerebellar-dependent motor learning. Although both TFs are highly expressed in granule neurons, transcriptomic analyses show MEF2D is the predominant genomic regulator of gene expression in vivo. Strikingly, genome-wide occupancy analyses reveal upon depletion of MEF2D, MEF2A occupancy robustly increases at a subset of sites normally bound to MEF2D. Importantly, sites experiencing compensatory MEF2A occupancy are concentrated within open chromatin and undergo functional compensation for genomic activation and gene expression. Finally, motor activity induces a switch from non-compensatory to compensatory MEF2-dependent gene regulation. These studies uncover genome-wide functional interdependency between paralogous TFs in the brain.

Graphical Abstract

In Brief

Majidi et al. study how transcription factors respond to paralog depletion by conditionally depleting MEF2A and MEF2D in mouse cerebellum. Depletion of MEF2D induces functionally compensatory genomic occupancy by MEF2A. Compensation occurs within accessible chromatin in a context-dependent manner. This study explores the interdependency between paralogous transcription factors.