title: Long Noncoding RNA FosDT Promotes Ischemic Brain Injury by Interacting with REST-Associated Chromatin-Modifying Proteins.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Surgery.
authors.forename: Suresh L
authors.initials: SL
authors.lastname: Mehta
authors.affiliation: Department of Neurological Surgery, Neuroscience Training Program, and.
authors.forename: TaeHee
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Neurological Surgery, Neuroscience Training Program, and Cellular and Molecular Pathology Training Program, University of Wisconsin, Madison, Wisconsin 53792 Vemuganti@neurosurgery.wisc.edu.
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics*; D056970:Co-Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016762:Genes, fos / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000473:pathology; D008297:Male; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D011597:Psychomotor Performance; D062085:RNA, Long Noncoding / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D020521:Stroke / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056970:Co-Repressor Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000099229:RE1-Silencing Transcription Factor; C000588854:CoREST protein, rat; C099683:SIN3A transcription factor
keywords: brain; gene expression; neuroprotection; noncoding RNA; stroke; transcriptional regulation