@article{47159bc3b71246b4b37886e3eb23d171,
title = "Chromatin Environment and Cellular Context Specify Compensatory Activity of Paralogous MEF2 Transcription Factors",
abstract = "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.",
keywords = "MEF2, cerebellum, chromatin, chromatin accessibility, compensation, gene expression, interdependency, learning, neuron, paralog, transcription factor",
author = "Majidi, {Shahriyar P.} and Reddy, {Naveen C.} and Moore, {Michael J.} and Hao Chen and Tomoko Yamada and Andzelm, {Milena M.} and Cherry, {Timothy J.} and Hu, {Linda S.} and Greenberg, {Michael E.} and Azad Bonni",
note = "Funding Information: We thank members of the Bonni, Greenberg, Gabel, Yang, and Yamada laboratories for helpful discussions and critical reading of the manuscript; and Matt Joens and Drs. Peter Bayguinov and James Fitzpatrick for electron microscopy (EM) studies and analyses at the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine , Children{\textquoteright}s Discovery Institute of Washington University , St. Louis Children{\textquoteright}s Hospital ( CDI-CORE-2015-505 ), and the Foundation for Barnes-Jewish Hospital ( 3770 ). We also thank Krikor Dikranian for insights in EM analyses and the Genome Technology Access Center (GTAC) and Center for Genomic Sciences (CGS) at Washington University in St. Louis for sequencing analyses. This work was supported by NIH grant NS041021 (A.B.), the Mathers Foundations (A.B.), and NIH grant R37 NS028829 (M.E.G.). Funding Information: We thank members of the Bonni, Greenberg, Gabel, Yang, and Yamada laboratories for helpful discussions and critical reading of the manuscript; and Matt Joens and Drs. Peter Bayguinov and James Fitzpatrick for electron microscopy (EM) studies and analyses at the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine, Children's Discovery Institute of Washington University, St. Louis Children's Hospital (CDI-CORE-2015-505), and the Foundation for Barnes-Jewish Hospital (3770). We also thank Krikor Dikranian for insights in EM analyses and the Genome Technology Access Center (GTAC) and Center for Genomic Sciences (CGS) at Washington University in St. Louis for sequencing analyses. This work was supported by NIH grant NS041021 (A.B.), the Mathers Foundations (A.B.), and NIH grant R37 NS028829 (M.E.G.). S.P.M. N.C.R. and A.B. designed the study and wrote the manuscript. S.P.M. performed all experiments. N.C.R. and S.P.M. performed bioinformatics analyses. M.J.M. and H.C. assisted with qPCR and immunohistochemistry. T.Y. contributed to biochemical experiments. M.M.A. T.J.C. L.S.H. and M.E.G. provided mice and purified reagents. The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = nov,
day = "12",
doi = "10.1016/j.celrep.2019.10.033",
language = "English",
volume = "29",
pages = "2001--2015.e5",
journal = "Cell Reports",
issn = "2211-1247",
number = "7",
}