# Probing the Protective Role of EZH2 in Epilepsy

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $504,791

## Abstract

Project Summary/Abstract
 Epilepsy is the 4th most prevalent neurological disorder after stroke, Alzheimer’s and migraine with an
incidence of 1 in 26 individuals. Though there are a number of anti-convulsant drugs available, there are no
anti-epileptogenic drugs that mitigate the progression of the disease. Using novel bioinformatic approaches,
we have identified an endogenous, protective program launched by the brain after a prolonged seizure that
functions to mitigate pathological changes.
 Epileptogenesis is associated with a plethora of changes in the brain including alterations in plasticity,
cell death, neurogenesis, inflammation and axonal sprouting. These changes occur over timescales ranging
from many minutes to years, but the orchestrating mechanisms are virtually unknown. Long-term changes in
gene expression that are associated with epileptogenesis imply that one or more master regulators of
transcription may be coordinating the brain alterations. In order to uncover these transcriptional mechanisms,
we turned to our recently published genome-wide expression datasets generated by the Epilepsy Microarray
Consortium (EMC). The datasets consist of mRNA expression profiles of rat dentate granule cells assayed at
various time points after Status Epilepticus (SE). Using a novel bioinformatic tool that integrates whole
genome transcription factor binding data with gene expression profiles, we analyzed datasets derived from
brains induced by 3 different convulsant stimuli, each in 2 independent labs, and at various time-points. This
analysis projected that Polycomb target genes represent the majority of chronically altered genes during
epileptogenesis. REST targets represent a second, overlapping, group of repressed genes. Polycomb is a
well-known driver of life-long changes in gene expression that works by epigenetically silencing genes across
the phyla. Our data shows an extremely robust induction of EZH2 protein (the catalytic methylase subunit of
Polycomb) over a 20 day window post SE in neurons. Further, we find that antagonizing EZH2 shortly after
SE robustly accelerates the onset of spontaneous recurrent seizures in mice, suggesting a protective rather
than pathological role for EZH2. How antagonism of EZH2 later after SE remains to be determined.
 In this project, we will test the hypothesis that an alteration in Polycomb output is a principal modifier of
epileptogenesis. We will ascertain whether EZH2 upregulation is always protective or whether its role evolves
during the latent period. We will test the effect of an order-of-magnitude change in EZH2 levels on corepressor
function to see whether such upregulation augments or hampers the repressive abilities of two major EZH2
containing complexes: Polycomb and REST. We anticipate that these studies will establish Polycomb as
a major orchestrator of the long-term changes associated with epileptogenesis. If so, approaches that
modulate Polycomb function may be of benefit to the 65 milli...

## Key facts

- **NIH application ID:** 9986046
- **Project number:** 5R01NS108756-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** RAYMOND J DINGLEDINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,791
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986046

## Citation

> US National Institutes of Health, RePORTER application 9986046, Probing the Protective Role of EZH2 in Epilepsy (5R01NS108756-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986046. Licensed CC0.

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