title: A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure.
abstract: Prader-Willi syndrome (PWS), a genetic disorder of obesity, intellectual disability and sleep abnormalities, is caused by loss of non-coding RNAs on paternal chromosome 15q11-q13. The imprinted minimal PWS locus encompasses a long non-coding RNA (lncRNA) transcript processed into multiple SNORD116 small nucleolar RNAs and the spliced exons of the host gene, 116HG. However, both the molecular function and the disease relevance of the spliced lncRNA 116HG are unknown. Here, we show that 116HG forms a subnuclear RNA cloud that co-purifies with the transcriptional activator RBBP5 and active metabolic genes, remains tethered to the site of its transcription and increases in size in post-natal neurons and during sleep. Snord116del mice lacking 116HG exhibited increased energy expenditure corresponding to the dysregulation of diurnally expressed Mtor and circadian genes Clock, Cry1 and Per2. These combined genomic and metabolic analyses demonstrate that 116HG regulates the diurnal energy expenditure of the brain. These novel molecular insights into the energy imbalance in PWS should lead to improved therapies and understanding of lncRNA roles in complex neurodevelopmental and metabolic disorders.
authors.affiliation: Medical Microbiology and Immunology, Genome Center, MIND Institute, University of California, Davis, CA 95616, USA.
authors.forename: Weston T
authors.initials: WT
authors.lastname: Powell
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Coulson
authors.forename: Florence K
authors.initials: FK
authors.lastname: Crary
authors.forename: Spencer S
authors.initials: SS
authors.lastname: Wong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ach
authors.forename: Peter
authors.initials: P
authors.lastname: Tsang
authors.forename: N
authors.initials: N
authors.lastname: Alice Yamada
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lasalle
mesh_terms: D000818:Animals; D001344:Autopsy; D001921:Brain / Q000503:physiopathology; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000503:physiopathology*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism*; D012890:Sleep / Q000235:genetics
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; C557020:RBBP5 protein, mouse; D062085:RNA, Long Noncoding; D056926:CLOCK Proteins