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

Shahriyar P. Majidi, Naveen C. Reddy, Michael J. Moore, Hao Chen, Tomoko Yamada, Milena M. Andzelm, Timothy J. Cherry, Linda S. Hu, Michael E. Greenberg, Azad Bonni

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)2001-2015.e5
JournalCell Reports
Volume29
Issue number7
DOIs
StatePublished - Nov 12 2019

Keywords

  • MEF2
  • cerebellum
  • chromatin
  • chromatin accessibility
  • compensation
  • gene expression
  • interdependency
  • learning
  • neuron
  • paralog
  • transcription factor

Fingerprint Dive into the research topics of 'Chromatin Environment and Cellular Context Specify Compensatory Activity of Paralogous MEF2 Transcription Factors'. Together they form a unique fingerprint.

  • Cite this

    Majidi, S. P., Reddy, N. C., Moore, M. J., Chen, H., Yamada, T., Andzelm, M. M., Cherry, T. J., Hu, L. S., Greenberg, M. E., & Bonni, A. (2019). Chromatin Environment and Cellular Context Specify Compensatory Activity of Paralogous MEF2 Transcription Factors. Cell Reports, 29(7), 2001-2015.e5. https://doi.org/10.1016/j.celrep.2019.10.033