Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance

Sci. Signal., 2 March 2010
Vol. 3, Issue 111, p. ra15
DOI: 10.1126/scisignal.2000502

Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance

  1. Martha Stapels1,*,
  2. Chelsea Piper2,*,
  3. Tao Yang2,,
  4. Minghua Li2,,
  5. Cheri Stowell2,3,,
  6. Zhi-gang Xiong2,,
  7. Julie Saugstad2,,
  8. Roger P. Simon2,§,
  9. Scott Geromanos1,
  10. James Langridge4,
  11. Jing-quan Lan2, and
  12. An Zhou2,§
  1. 1Waters Corporation, Milford, MA 01757, USA.
  2. 2Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA.
  3. 3Discoveries in Sight, Legacy Research, Portland, OR 97232, USA.
  4. 4Waters Corporation, Manchester M22 5PP, UK.
  1. §To whom correspondence should be addressed. E-mail: azhou{at}downeurobiology.org (A.Z.) and rsimon{at}downeurobiology.org (R.P.S.).
  • * These authors contributed equally to this work as first authors.

  • These authors contributed equally to this work as second authors.

  • These authors contributed equally to this work as third authors.

Abstract

Exposing the brain to sublethal ischemia affects the response to a subsequent, otherwise injurious ischemia, resulting in transcriptional suppression and neuroprotection, a response called ischemic tolerance. Here, we show that the proteomic signature of the ischemic-tolerant brain is characterized by increased abundance of transcriptional repressors, particularly polycomb group (PcG) proteins. Knocking down PcG proteins precluded the induction of ischemic tolerance, whereas in an in vitro model, overexpressing the PcG proteins SCMH1 or BMI1 induced tolerance to ischemia without preconditioning. We found that PcG proteins are associated with the promoter regions of genes encoding two potassium channel proteins that show decreased abundance in ischemic-tolerant brains. Furthermore, PcG proteins decreased potassium currents in cultured neuronal cells, and knocking down potassium channels elicited tolerance without preconditioning. These findings reveal a previously unknown mechanism of neuroprotection that involves gene repressors of the PcG family.

Citation:

M. Stapels, C. Piper, T. Yang, M. Li, C. Stowell, Z.-g. Xiong, J. Saugstad, R. P. Simon, S. Geromanos, J. Langridge, J.-q. Lan, and A. Zhou, Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance. Sci. Signal. 3, ra15 (2010).

Post-Conditioning and Reperfusion Injury in the Treatment of Stroke
R. Simon
Dose-Response 12, dose-response.14-026.Simo-dose-response.14-026.Simo (1 October 2014)

Reprogramming the Response to Stroke by Preconditioning
S. L. Stevens, K. B. Vartanian, and M. P. Stenzel-Poore
Stroke 45, 2527-2531 (1 August 2014)

Nascent Proteomes in Peripheral Blood Mononuclear Cells as a Novel Source for Biomarker Discovery in Human Stroke
F. Bian, R. P. Simon, Y. Li, L. David, J. Wainwright, C. L. Hall, M. Frankel, and A. Zhou
Stroke 45, 1177-1179 (1 April 2014)

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death
K.-M. Noh, J.-Y. Hwang, A. Follenzi, R. Athanasiadou, T. Miyawaki, J. M. Greally, M. V. L. Bennett, and R. S. Zukin
Proc. Natl. Acad. Sci. USA 109, E962-E971 (17 April 2012)

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance
S. F. C. Miller-Delaney, S. Das, T. Sano, E. M. Jimenez-Mateos, K. Bryan, P. G. Buckley, R. L. Stallings, and D. C. Henshall
J. Neurosci. 32, 1577-1588 (1 February 2012)

Can Genes Modify Stroke Outcome and By What Mechanisms?
R. P. Simon, R. Meller, A. Zhou, and D. Henshall
Stroke 43, 286-291 (1 January 2012)

Remote Ischemic Preconditioning: Making the Brain More Tolerant, Safely and Inexpensively
M. A. Moskowitz, and C. Waeber
Circulation 123, 709-711 (22 February 2011)

Science Signaling Podcast: 4 January 2011
M. B. Yaffe, and A. M. VanHook
Sci Signal 4, pc1-pc1 (4 January 2011)

Eradicating the Mediators of Neuronal Death with a Fine-Tooth Comb
R. S. Zukin, and A. M. VanHook
Sci Signal 3, pe20-pe20 (8 June 2010)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882