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Human Molecular Genetics Advance Access originally published online on August 5, 2009
Human Molecular Genetics 2009 18(22):4227-4238; doi:10.1093/hmg/ddp373
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Karen N. Leung1, Roxanne O. Vallero1, Amanda J. DuBose2, James L. Resnick2 and Janine M. LaSalle1,*

1 Microbiology and Immunology and Rowe Program in Human Genetics, UC Davis School of Medicine, Davis, CA 95616, USA and 2 Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32601, USA

* To whom correspondence should be addressed at: Medical Microbiology and Immunology, One Shields Avenue, Davis, CA 95616, USA. Tel: +1 5307547598; Fax: +1 5307528692; Email: jmlasalle{at}ucdavis.edu

Received June 10, 2009; Revised July 24, 2009; Accepted August 3, 2009

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.


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