LncRNA SNHG14 Regulates the Expression of BDNF by Recruiting Histone Methyltransferase EZH2 to Mediate H3K27me3, Thereby Affecting Angiogenesis and Functional Recovery After Cerebral Ischemia.

We aimed to probe the role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) on angiogenesis and functional recovery after cerebral ischemia (CI) by recruiting histone methyltransferase enhancer zeste homolog 2 (EZH2) to mediate trimethylation of lysine 27 on histone H3 (H3K27me3) and thus modulate brain-derived neurotrophic factor (BDNF) expression. The Zea Longa method was employed to establish a rat model of right middle cerebral artery occlusion (MCAO). Longa method was applied to assess the neurological deficits in rats; ELISA was adopted to test the levels of inflammatory factors (interleukin (IL)-1β, IL-6, and IL-8) in the cortical tissue of the ischemic penumbra; HE staining and TUNEL staining were implemented to observe the pathological changes and apoptosis in the ischemic penumbra cortex; and immunohistochemistry staining was implemented to observe the CD34 positive expression level and microvascular density (MVD) in the ischemic penumbra cortex. The expression levels of SNHG14, EZH2, and BDNF in the cortical tissue of the ischemic penumbra were determined by RT-qPCR or WB, and the interactions among KCNQ1OT1, EZH2, and TIMP-3 were verified by RNA-pull down, RIP, and ChIP experiments. Increased levels of SNHG14 and EZH2 were observed in the cortical tissue of the ischemic penumbra in MCAO rats, accompanied by decreased BDNF levels. Both downregulation of SNHG14 and downregulation of EZH2 ameliorated neurological deficits in CI rats, reduced the level of inflammatory factors and apoptosis, alleviated damage to the cortical tissue of the ischemic penumbra, and increased MVD. Upregulation of EZH2 or downregulation of BDNF reversed the improvement effects of SNHG14 downregulation on neurological function and angiogenesis in CI rats. Mechanistically, SNHG14 could mediate H3K27me3 and thus inhibit BDNF expression by recruiting EZH2. Downregulation of SNHG14 ameliorates neurological function and angiogenesis in CI rats through the EZH2/BDNF axis.