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Transcription Factor TFAP2B Exerts Neuroprotective Effects Targeting BNIP3-Mediated Mitophagy in Ischemia/Reperfusion
Yong Peng1, Jiaoying Jia1, Mingming Zhang1
1Department of Neurosurgery, The Second Xiangya Hospital of Central South University, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, People's Republic of China.
Abstract:
Cerebral ischemia-reperfusion injury (CIRI) leads to malignant brain edema, blood-brain barrier destruction, and neuronal apoptosis. N6-methyladenosine (m6A) RNA modification in CIRI was still limited explored. In this study, MeRIP- and RNA-sequencing were performed of middle cerebral artery occlusion and reperfusion (MCAO/R) rats to find novel potential molecular targets. Transcription factor TFAP2B stood out of which its m6A abundance decreased associated with a marked reduction of its mRNA based on cojoint interactive bioinformatics analysis of the MeRIP- and RNA-sequencing data. It was suggested TFAP2B could have a role in CIRI. Functionally, overexpression of TFAP2B in cultured primary neurons could effectively improve the cell survival and pro-survival autophagy in parallel with reduced cell apoptosis during OGD/R in vitro. Through the RNA-sequencing of TFAP2B overexpressed primary neurons and subsequent validation experiments, it was found that mitophagy receptor BNIP3 was one of the important targets of TFAP2B in OGD/R neurons through which TFAP2B could bind to its promoter region for transcriptional activation of BNIP3, thereby enhancing BNIP3-mediated mitophagy to protect against OGD/R injury of neurons. Lastly, TFAP2B was demonstrated to alleviate the MCAO/R damage to a certain extent in vivo. Although it failed to confirm TFAP2B dysregulation was m6A dependent in current research, this is the first research of TFAP2B in CIRI field with important guiding significance.
Insights
Transcription factor TFAP2B protects neurons from cerebral ischemia-reperfusion injury (CIRI) by activating mitophagy. This study identifies TFAP2B as a potential therapeutic target for brain injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cerebral ischemia-reperfusion injury (CIRI) causes severe brain damage, including edema, blood-brain barrier disruption, and neuronal apoptosis.
- The role of N6-methyladenosine (m6A) RNA modification in CIRI is not well understood.
- Identifying novel molecular targets is crucial for developing effective CIRI treatments.
Purpose of the Study:
- To investigate the role of m6A RNA modification and identify potential molecular targets in CIRI.
- To explore the function of transcription factor TFAP2B in the context of CIRI.
- To elucidate the underlying molecular mechanisms by which TFAP2B exerts its protective effects.
Main Methods:
- Middle cerebral artery occlusion and reperfusion (MCAO/R) in rats.
- MeRIP-sequencing and RNA-sequencing.
- Bioinformatic analysis of sequencing data.
- In vitro oxygen-glucose deprivation/reperfusion (OGD/R) models using primary neurons.
- TFAP2B overexpression and validation experiments.
- In vivo MCAO/R models.
Main Results:
- TFAP2B expression and m6A abundance were reduced in MCAO/R rats.
- TFAP2B overexpression in neurons reduced apoptosis and enhanced autophagy during OGD/R.
- TFAP2B directly activated the transcription of mitophagy receptor BNIP3.
- TFAP2B enhanced BNIP3-mediated mitophagy, protecting neurons from OGD/R injury.
- TFAP2B alleviated MCAO/R damage in vivo.
Conclusions:
- TFAP2B plays a protective role in CIRI by promoting BNIP3-mediated mitophagy.
- TFAP2B is a potential therapeutic target for treating brain injury following ischemia-reperfusion.
- Further research is needed to confirm the m6A dependence of TFAP2B dysregulation in CIRI.
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