Increased Binding of Stroke-Induced Long Non-Coding RNAs to the Transcriptional Corepressors Sin3A and coREST

Abstract

LncRNAs (long non-coding RNAs) are thought to play a significant role in cellular homeostasis during development and disease by interacting with CMPs (chromatin-modifying proteins). We recently showed that following transient focal ischemia, the expression of many lncRNAs was altered significantly in rat brain. We currently analyzed whether focal ischemia also alters the association of lncRNAs with the CMPs Sin3A and coREST (corepressors of the RE-1 silencing transcription factor). RIP (RNA immunoprecipitation) combined with lncRNA microarray analysis showed that 177 of the 2497 lncRNAs expressed in rat cerebral cortex showed significantly increased binding to either Sin3A or coREST following ischemia compared with sham. Of these, 26 lncRNAs enriched with Sin3A and 11 lncRNAs enriched with coREST were also up-regulated in their expressions after ischemia. A majority of the lncRNAs enriched with these CMPs were intergenic in origin. Evaluation of the expression profiles of corresponding protein-coding genes showed that their expression levels correlate with those of the lncRNAs with which they shared a common locus. This is the first study to show that stroke-induced lncRNAs might associate with CMPs to modulate the post-ischemic epigenetic landscape.

Non-coding RNAs and neuroprotection after acute CNS injuries

“…Functional significance of the lncRNAs in post-stroke outcome is currently not known, however they might play a significant role in modifying the post-stroke epigenetic landscape. In support of this notion, a study from our lab showed that binding of many stroke-responsive lncRNAs to chromatin-modifying proteins (CMPs) Sin3A and coREST increases significantly after focal ischemia (Dharap et al, 2013). These 2 CMPs are co-repressors of the transcription factor REST which is known to promote ischemic neuronal death (Noh et al, 2012; Pandi et al, 2013; Hwang et al, 2014; Mehta et al, 2015).…”

Non-coding RNAs in cerebral endothelial pathophysiology: Emerging roles in stroke

“…In addition to miRNAs, the research group led by Dr. Vemuganti has recently published a series of pioneering studies, demonstrating that cerebral ischemia rapidly changes the expression profiles of other classes of ncRNAs, such as lncRNAs (Dharap et al, 2012; Dharap et al, 2013; Vemuganti, 2013) and piRNAs (Dharap et al, 2011), and imply that manipulation of these ncRNAs may regulate post-ischemic neuronal death and remodeling. To our knowledge, little is known regarding the expression and function of cerebral vasculature and/or endothelium lncRNA and piRNA molecules responsible for stroke.…”

“…So far in the stroke field, the role of a specific class of small ncRNAs, miRNAs, was mainly investigated (Rink and Khanna, 2010; Saugstad, 2010; Vemuganti, 2010; Tan et al, 2011; Eacker et al, 2013; Liu et al., 2013; Ouyang et al, 2013; Yin et al, 2013a). Moreover, recent breakthrough microarray profiling studies identifying stroke-responsible alteration of piRNAs (Dharap et al, 2011) and lncRNAs (Dharap et al, 2012; Dharap et al, 2013; Vemuganti, 2013) underscore the importance of other ncRNAs in the pathogenesis of ischemic stroke. In this review, we will discuss the functional significance of stroke-associated endothelial ncRNAs with a special focus on miRNAs in cerebral endothelial pathophysiology after stroke.…”

Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia

“…Involvement of lncRNA in human diseases, including stroke, have begun to appear and are expected to escalate. For example, recent microarray profiling studies identifying stroke-responsive alterations of lncRNAs (Dharap et al, 2012; Dharap et al, 2013; Vemuganti, 2013) underscore the importance of lncRNAs in the pathogenesis of ischemic stroke. However, the essential role and molecular mechanisms of lncRNA in ischemic stroke still remain poorly understood.…”