title: Neuroprotective effects of a chromatin modifier on ischemia/reperfusion neurons: implication of its regulation of BCL2 transactivation by ERα signaling.
abstract: An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERα)-mediated neuroprotective effects is valuable for the development of therapeutic strategy against neuronal ischemic injury. Here, we report the upregulated expression of metastasis-associated protein 1 (MTA1), a master chromatin modifier and transcriptional regulator, in the murine middle cerebral artery occlusion (MCAO) model. Inhibition of MTA1 expression by in vivo short interfering RNA treatment potentiated neuronal apoptosis in a caspase-3-dependent manner and thereafter aggravated MCAO-induced neuronal damage. Mechanistically, the pro-survival effects of MTA1 required the participation of ERα signaling. We also provide in vitro evidence that MTA1 enhances the binding of ERα with the BCL2 promoter upon ischemic insults via recruitment of HDAC2 together with other unidentified coregulators, thus promoting the ERα-mediated transactivation of the BCL2 gene. Collectively, our results suggest that the augmentation of endogenous MTA1 expression during neuronal ischemic injury acts additionally to an endocrinous cascade orchestrating intimate interactions between ERα and BCL2 pathways and operates as an indispensable defensive mechanism in response to neuronal ischemia/reperfusion stress. Future studies in this field will shed light on the modulation of the complicated neuroprotective effects by estrogen signaling.
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Hong-Zeng
authors.initials: HZ
authors.lastname: Li
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Neurology, General Hospital of Shenyang Military Command, Shenyang, 110015, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Histology and Embryology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Histology and Embryology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China. liweipepeyato@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China. zhaotianzhi1981@163.com.
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D006655:Histone Deacetylases
keywords: Estrogen receptor alpha (ERα); Histone deacetylase (HDAC); Ischemia/reperfusion (I/R); Metastasis-associated protein 1 (MTA1); Neuron