METTL3-deficiency Suppresses Neural Apoptosis to Induce Protective Effects in Cerebral I/R Injury via Inhibiting RNA m6A Modifications: A Pre-clinical and Pilot Study

• Published in: Neurochemical research Vol. 49; no. 1; pp. 85 - 98
• Main Authors: Huang, Gang, Qiu, Yuda, Fan, Yafei, Liu, Jianfeng
• Format: Journal Article
• Language: English
• Published: New York Springer US 2024; Springer Nature B.V
• Subjects: Animal models; Animal tissues; Apoptosis; Astrocytes; Biochemistry; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell culture; Cell cycle; Cerebral blood flow; Down-regulation; Hypoxia-inducible factor 1a; Injuries; Ischemia; Methyltransferase; N6-methyladenosine; Neurochemistry; Neurology; Neurosciences; Occlusion; Original Paper; Oxidative stress; Reperfusion; Ribonucleic acid; RNA; Oxidative stress; LncRNA ABHD11-AS1; N6-Methyladenosine; Cerebral I/R injury; METTL3; Cell apoptosis; cell cycle arrest
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-023-04015-6

N6-Methyladenosine (m6A) RNA methylation involves in regulating the initiation, progression and aggravation of cerebral ischemia-reperfusion (I/R) injury, however, the detailed functions and mechanisms by which m6A drives cerebral I/R injury are not fully understood. This study found that methyltransferase-like 3 (METTL3) m6A-dependently regulated cerebral I/R injury trough regulating a novel LncRNA ABHD11-AS1/miR-1301-3p/HIF1AN/HIF-1α axis. Specifically, the middle cerebral artery occlusion (MCAO)/reperfusion mice models and glucose deprivation (OGD)/reoxygenation (RX) astrocyte cell models were respectively established, and we verified that METTL3, ABHD11-AS1 and HIF1AN were upregulated, whereas miR-1301-3p and HIF-1α were downregulated in both MCAO/reperfusion mice tissues and OGD/RX astrocytes. Mechanical experiments confirmed that METTL3 m6A dependently increased stability and expression levels of ABHD11-AS1, and elevated ABHD11-AS1 sponged miR-1301-3p to upregulate HIF1AN, resulting in the downregulation of HIF-1α. Moreover, silencing of METTL3 rescued MCAO/reperfusion and OGD/RX-induced oxidative stress-associated cell apoptosis and cell cycle arrest in both mice brain tissues in vivo and the mouse primary astrocytes in vitro, which were abrogated by overexpressing ABHD11-AS1 and downregulating miR-1301-3p. Taken together, our study firstly reported a novel METTL3/m6A/ ABHD11-AS1/miR-1301-3p/HIF1AN/HIF-1α signaling cascade in regulating the progression of cerebral I/R injury, and future work will focus on investigating whether the above genes can be used as biomarkers for the treatment of cerebral I/R injury by performing clinical studies.