Human Molecular Genetics, Vol 8, 555-566, Copyright © 1999 by Oxford University Press
J Schweizer, D Zynger and U Francke
Human chromosome region 15q11-q13 contains a cluster of oppositely
imprinted genes. Loss of the paternal or the maternal alleles by deletion
of the region or by uniparental disomy 15 results in Prader- Willi syndrome
(PWS) or Angelman syndrome (AS), respectively. Hence, the two
phenotypically distinct neurodevelopmental disorders are caused by the lack
of products of imprinted genes. Subsets of PWS and AS patients exhibit
'imprinting mutations', such as small microdeletions within the 5' region
of the small nuclear ribonucleoprotein polypeptide N ( SNRPN )
transcription unit which affect the transcriptional activity and
methylation status of distant imprinted genes throughout 15q11-q13 in cis.
To elucidate the mechanism of these long-range effects, we have analyzed
the chromatin structure of the 150 kb SNRPN transcription unit for DNase I-
and Msp I-hypersensitive sites. By using an in vivo approach on
lymphoblastoid cell lines from PWS and AS individuals, we discovered that
the SNRPN exon 1 is flanked by prominent hypersensitive sites on the
paternal allele, but is completely inaccessible to nucleases on the
maternal allele. In contrast, we identified several regions of increased
nuclease hypersensitivity on the maternal allele, one of which coincides
with the AS minimal microdeletion region and another lies in intron 1
immediately downstream of the paternal-specific hypersensitive sites. At
several sites, parental origin-specific nuclease hypersensitivity was found
to be correlated with hypermethylation on the allele contributed by the
other parent. The differential parental origin- dependent chromatin
conformations might govern access of regulatory protein complexes and/or
RNAs which could mediate interaction of the region with other genes.
ARTICLES
In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit
Howard Hughes Medical Institute and Department of Genetics, Stanford University School of Medicine, Stanford CA 94305-5323, USA.
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