Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance.
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.
Stapels
Martha
M
Waters Corporation, Milford, MA 01757, USA.
Piper
Chelsea
C
Yang
Tao
T
Li
Minghua
M
Stowell
Cheri
C
Xiong
Zhi-gang
ZG
Saugstad
Julie
J
Simon
Roger P
RP
Geromanos
Scott
S
Langridge
James
J
Lan
Jing-quan
JQ
Zhou
An
A
D000818:Animals; D001483:Base Sequence; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology*; D044127:Epigenesis, Genetic; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C489421:Bmi1 protein, mouse; C496982:Kcna5 protein, mouse; C101328:Kcnab2 protein, mouse; D051666:Kv1.5 Potassium Channel; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C570430:Scmh1 protein, mouse; D051637:Shaker Superfamily of Potassium Channels; D063150:Polycomb Repressive Complex 1