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

Autor:	Majidi SP; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; MD-PhD Program, Washington University School of Medicine, St. Louis, MO 63110, USA., Reddy NC; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Moore MJ; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Chen H; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA., Yamada T; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan., Andzelm MM; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA., Cherry TJ; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, 1900 9(th) Ave., Seattle, WA 98101, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA., Hu LS; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA., Greenberg ME; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA., Bonni A; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bonni@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2019 Nov 12; Vol. 29 (7), pp. 2001-2015.e5.
DOI:	10.1016/j.celrep.2019.10.033
Abstrakt:	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. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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