The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease.
The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered in the cytoplasm in part through binding to huntingtin. Polyglutamine expansions in huntingtin, which causes Huntington's disease (HD), abrogates REST-huntingtin binding. Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences and decreases neuronal gene expression. In this work, we found that levels of several microRNAs (miRNAs) with upstream RE1 sites are decreased in HD patient cortices relative to healthy controls. Interestingly, one of these, the bifunctional brain enriched miR-9/miR-9*, targets two components of the REST complex: miR-9 targets REST and miR-9* targets CoREST. These data provide evidence for a double negative feedback loop between the REST silencing complex and the miRNAs it regulates.
Packer
Amy N
AN
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Xing
Yi
Y
Harper
Scott Q
SQ
Jones
Lesley
L
Davidson
Beverly L
BL
D020413:3' Untranslated Regions / Q000502:physiology; D000368:Aged; D001921:Brain / Q000378:metabolism*; D002461:Cell Line, Transformed; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D035683:MicroRNAs / Q000494:pharmacology / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011180:Postmortem Changes; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D000099229:RE1-Silencing Transcription Factor
D020413:3' Untranslated Regions; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C121019:RCOR1 protein, human