Long non-coding RNA mediates stroke-induced neurogenesis.

Neurogenesis contributes to post-stroke recovery. Long non-coding RNAs (lncRNAs) participate in the regulation of stem cell self-renewal and differentiation. However, the role of lncRNAs in stroke-induced neurogenesis remains unknown. In this study, we found that H19 was the most highly upregulated lncRNA in neural stem cells (NSCs) of the subventricular zone (SVZ) of rats subjected to focal cerebral ischemia. Deletion of H19 suppressed cell proliferation, promoted cell death and blocked NSC differentiation. RNA sequencing analysis revealed that genes deregulated by H19 knockdown were those that are involved in transcription, apoptosis, proliferation, cell cycle and response to hypoxia. H19 knockdown significantly increased the transcription of cell cycle-related genes including p27, whereas overexpression of H19 substantially reduced expression of these genes through the interaction with chromatin remodeling proteins EZH2 and SUZ12. Moreover, H19 regulated neurogenesis-related miRNAs. Inactivation of H19 in NSCs of ischemic rats attenuated spontaneous functional recovery after stroke. Collectively, our data provide novel insights into the epigenetic regulation of lncRNAs in stroke-induced neurogenesis. (c) AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Adult neurogenesis contributes to neurological function. Elucidating the underlying molecular mechanisms in post-stroke neurogenesis could provide new therapies to amplify endogenous neurogenesis and to improve neurological function during stroke recovery. The present study for the first time reveals that stroke substantially changes lncRNA profiles and lncRNA-mRNA co-expression networks in the neural stem cells. Furthermore, we demonstrate that lncRNA H19 mediates stroke-augmented neurogenesis by recruiting chromatin remodeling proteins and regulating microRNA expression to modulate neurogenesis-related transcription. Our results provide new insights into the epigenetic control of adult neurogenesis after cerebral ischemia.