Long noncoding RNA MEG3 activation of p53 mediates ischemic neuronal death in stroke

•We first confirmed the expression and function of long noncoding RNA maternally expressed gene 3 (MEG3) in ischemia.•MEG3 binds with p53-DBD271-282 which stimulates p53-mediated transactivation and mediates ischemic neuronal death.•Intervention of MEG3-p53 interaction by administration of Tat-p53-DBD271-282 protects against ischemic insults.

Maternally expressed gene 3 (MEG3) is suggested to function as a long non-coding RNA (lncRNA) and to play roles in various human cancers. However, the functional properties of MEG3 in ischemic stroke remain unknown. Here, we report that expression of MEG3 is upregulated following ischemia in adult mice. Moreover, cerebral ischemia recruits p53 into the MEG3 complex in ischemic tissues. MEG3 directly binds with the p53 DNA binding domain (DBD) consisting of amino acids 271-282 (p53-DBD271-282), which stimulates p53-mediated transactivation and mediates ischemic neuronal death. Administration of the membrane-permeable peptide inhibitor Tat-p53-DBD271-282 uncouples p53 from MEG3 in vivo and protects against cerebral ischemic insults in vitro and in vivo. Our data demonstrate that MEG3 functions as a cell death promoter in ischemia and physically and functionally interacts with p53 to mediate ischemic damage. Intervention in the MEG3-p53 interaction presents a new target for the therapeutic treatment of ischemic insults.