Long Noncoding RNA FosDT Promotes Ischemic Brain Injury by Interacting with REST-Associated Chromatin-Modifying Proteins.

Ischemia induces extensive temporal changes in cerebral transcriptome that influences the neurologic outcome after stroke. In addition to protein-coding RNAs, many classes of noncoding RNAs, including long noncoding RNAs (LncRNAs), also undergo changes in the poststroke brain. We currently evaluated the functional significance of an LncRNA called Fos downstream transcript (FosDT) that is cogenic with Fos gene. Following transient middle cerebral artery occlusion (MCAO) in adult rats, expression of FosDT and Fos was induced. FosDT knockdown significantly ameliorated the postischemic motor deficits and reduced the infarct volume. Focal ischemia also increased FosDT binding to chromatin-modifying proteins (CMPs) Sin3a and coREST (corepressors of the transcription factor REST). Furthermore, FosDT knockdown derepressed REST-downstream genes GRIA2, NFκB2, and GRIN1 in the postischemic brain. Thus, FosDT induction and its interactions with REST-associated CMPs, and the resulting regulation of REST-downstream genes might modulate ischemic brain damage. LncRNAs, such as FosDT, can be therapeutically targeted to minimize poststroke brain damage.

Significance statement: Mammalian brain is abundantly enriched with long noncoding RNAs (LncRNAs). Functional roles of LncRNAs in normal and pathological states are not yet understood. This study identified that LncRNA FosDT induced after transient focal ischemia modulates poststroke behavioral deficits and brain damage. These effects of FosDT in part are due to its interactions with chromatin-modifying proteins Sin3a and coREST (corepressors of the transcription factor REST) and subsequent derepression of REST-downstream genes GRIA2, NFκB2, and GRIN1. Therefore, LncRNA-mediated epigenetic remodeling could determine stroke outcome.