Deletion of imprinted human chromosomal locus 15q11-q13 leads to two disorders: Prader-Willi syndrome and Angelman syndrome. The differentially methylated Prader-Willi syndrome imprinting control region (ICR) controls allele-specific expression in the locus and serves as a promoter for a long transcript expressed from the unmethylated paternal allele. The long, non-coding transcript begins at the PWS-ICR to give rise to the Snrpn mRNA and terminates antisense to the gene Ube3a. The transcript is processed into multiple RNA products and expression of the full-length transcript is regulated in a cell-type specific manner, such that a long, non-coding portion is expressed only in neurons. The long, non-coding portion of the transcript is comprised of tandem repeats called Snord116 and Snord115 and Ube3a-antisense. Loss of the repeated Snord116 transcript causes Prader-Willi syndrome, but the molecular function of the RNA from Snord116 region is unknown. The primary transcript arising from the Snord116 locus consists of repeated exons that are spliced to form 116HG and introns that are exonucleolytically digested to give rise to Snord116 C/D box snoRNAs. Here we show that 116HG forms a nuclear RNA cloud that diurnally regulates transcription of 6,000 genes important for regulation of diurnal energy expenditure. Accumulation of the 116HG RNA cloud in early postnatal neurons coincides with a previously described allele-specific chromatin decondensation of unknown mechanism. Additionally, we show that transcription in the Snord116 region leads to RNA:DNA hybrid formation and loss of nucleosomes. However, induction of excess formation of RNA:DNA hybrids in the Snord116 region by a topoisomerase inhibitor causes early termination of transcription and inhibition of Ube3a-antisense expression. While previous work has focused on epigenetic mechanisms controlling transcription in this locus, these results suggest that show that transcription and the RNA products of the Prader-Willi locus may regulate epigenetic features of postnatal neurons genome-wide.
|Advisor:||LaSalle, Janine M.|
|Commitee:||Chedin, Frederic, Segal, David|
|School:||University of California, Davis|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- California|
|Source:||DAI-B 74/10(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Biochemistry|
|Keywords:||Chromatin biology, Epigenetics, Long, Neurodevelopment, Non-coding rna, Prader-willi syndrome, Transcription|
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