Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size

Karen N. Leung, Roxanne O. Vallero, Amanda J. Dubose, James L. Resnick, Janine M LaSalle

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Imprinting, non-coding RNA and chromatin organization are modes of epigenetic regulation that modulate gene expression and are necessary for mammalian neurodevelopment. The only two known mammalian clusters of genes encoding small nucleolar RNAs (snoRNAs), SNRPN through UBE3A (15q11-q13/7qC) and GTL2 (14q32.2/12qF1), are neuronally expressed, localized to imprinted loci and involved in at least five neurodevelopmental disorders. Deficiency of the paternal 15q11-q13 snoRNA HBII-85 locus is necessary to cause the neurodevelopmental disorder Prader-Willi syndrome (PWS). Here we show epigenetically regulated chromatin decondensation at snoRNA clusters in human and mouse brain. An 8-fold allele-specific decondensation of snoRNA chromatin was developmentally regulated specifically in maturing neurons, correlating with HBII-85 nucleolar accumulation and increased nucleolar size. Reciprocal mouse models revealed a genetic and epigenetic requirement of the 35 kb imprinting center (IC) at the Snrpn-Ube3a locus for transcriptionally regulated chromatin decondensation. PWS human brain and IC deletion mouse Purkinje neurons showed significantly decreased nucleolar size, demonstrating the essential role of the 15q11-q13 HBII-85 locus in neuronal nucleolar maturation. These results are relevant to understanding the molecular pathogenesis of multiple human neurodevelopmental disorders, including PWS and some causes of autism.

Original languageEnglish (US)
Pages (from-to)4227-4238
Number of pages12
JournalHuman Molecular Genetics
Volume18
Issue number22
DOIs
StatePublished - 2009

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Small Nucleolar RNA
Prader-Willi Syndrome
Chromatin
Epigenomics
snRNP Core Proteins
Untranslated RNA
Purkinje Cells
Brain
Gene Expression Regulation
Multigene Family
Autistic Disorder
Alleles
Neurons
Imprinting (Psychology)
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size. / Leung, Karen N.; Vallero, Roxanne O.; Dubose, Amanda J.; Resnick, James L.; LaSalle, Janine M.

In: Human Molecular Genetics, Vol. 18, No. 22, 2009, p. 4227-4238.

Research output: Contribution to journalArticle

Leung, Karen N. ; Vallero, Roxanne O. ; Dubose, Amanda J. ; Resnick, James L. ; LaSalle, Janine M. / Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 22. pp. 4227-4238.
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