A systems approach identifies Enhancer of Zeste Homolog 2 (EZH2) as a protective factor in epilepsy

Autoři: Nadia Khan aff001;  Barry Schoenike aff002;  Trina Basu aff002;  Heidi Grabenstatter aff004;  Genesis Rodriguez aff005;  Caleb Sindic aff005;  Margaret Johnson aff002;  Eli Wallace aff006;  Rama Maganti aff007;  Raymond Dingledine aff008;  Avtar Roopra aff002
Působiště autorů: Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff001;  Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff002;  Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff003;  Department of Integrative Physiology, University of Colorado-Boulder, Boulder, Colorado, United States of America aff004;  College of Letters and Science, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff005;  Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff006;  Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff007;  Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, United States of America aff008
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226733


Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after status epilepticus (SE) robustly increases spontaneous seizure burden weeks later. This suggests that EZH2 upregulation is a protective. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.

Klíčová slova:

Epilepsy – Factor analysis – Gene expression – Gene regulation – Mice – Mouse models – Transcription factors – Transcriptome analysis


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