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.
Due to the diverse states a neuron undergoes during development and plasticity, the context-dependent nature of compensation by TF family members should advance our understanding of brain development and function. As we learn more about the interdependency of paralogous TFs, we should gain further insight into how paralogs respond to TF loss-of-function mutations in the context of disease […]
Furthermore, identifying the genomic signatures of non-compensatory sites may allow us to predict regulatory elements that might be more susceptible to gene dysregulation upon perturbation of different TF paralogs in disease states.
Common Design 