Osman El-Maarri,1, 7, 8, Karin Buiting 3, 8, Edwin G. Peery 4, Peter M. Kroisel 5, Basak Balaban 6, Klaus Wagner 5, Bulent Urman 6, Julia Heyd 1, Christina Lich 3, Camilynn I. Brannan 4, Jörn Walter 1, 2 & Bernhard Horsthemke 3
1 Max-Planck-Institut für Molekulare Genetik, Berlin,
Germany.
2 Present address: Universität des Saarlandes, Genetik,
Postfach 151150, Saarbrücken, Germany.
3 Institut für Humangenetik, Universitätsklinikum
Essen, Essen, Germany.
4 Department of Molecular Genetics and Microbiology,
Center for Mammalian Genetics, and the University of Florida Brain Institute,
University of Florida College of Medicine, Gainesville, Florida, USA.
5 Institute of Medical Biology & Human Genetics,
University of Graz Harrachgasse 21/8, Graz, Austria.
6 Assisted Reproductive Technology Unit, Amerikan Hastanasi,
Güzelbahce 20 80200 Nisantasi, Istanbul, Turkey.
7 Present address: Institute of Experimental Haematology
and Transfusion Medicine, Bonn, Germany.
8 These authors contributed equally to this work.
Correspondence should be addressed to J. Walter.
e-mail: j.walter@mx.uni-saarland.de
Prader-Willi syndrome (PWS) is a neurogenetic disorder
that results from the lack of transcripts expressed from the paternal copy
of the imprinted chromosomal region 15q11–q13 [refs. 1,
2].
In some patients, this is associated with a deletion of the SNURF-SNRPN
exon 1 region inherited from the paternal grandmother and the presence
of a maternal imprint on the paternal chromosome. Assuming that imprints
are reset in the germ line, we and others have suggested that this region
constitutes part of the 15q imprinting center (IC) and is important for
the maternal to paternal imprint switch in the male germ line [3,
4]. Here we report that sperm DNA from two males with
an IC deletion had a normal paternal methylation pattern along 15q11–q13.
Similar findings were made in a mouse model. Our results indicate that
the incorrect maternal methylation imprint in IC deletion patients is established
de novo after fertilization. Moreover, we found that CpG-rich regions in
SNURF-SNRPN and NDN, which in somatic tissues are methylated on the maternal
allele, are hypomethylated in unfertilized human oocytes. Our results indicate
that the normal maternal methylation imprints in 15q11–q13 also are established
during or after fertilization.
...
Our data show that imprinting human 15q11-q13 involves a more complex scenario and different developmental timing than previously envisaged [1, 11, 12]. If maternal methylation imprints on human chromosome 15 are established or completed after fertilization, how might the two parental chromosomes be distinguished in the zygote? One explanation is that imprinting signals other than methylation, such as heritable alterations in chromatin structure, are marking the male and female alleles. These differences could then be recognized after fertilization and translated into stable methylation imprints. Another possibility is that methylation differences at other, undetected loci carry the parental chromosomal mark, which leads to de novo methylation at neighboring loci in the early embryo. But the SNURF-SNRPN region analyzed is part of the IC, is especially CpG-rich, is conserved between human and mouse, carries the minimal elements for imprinting as determined by transgenic studies [13], and is epigenetically active in Drosophila melanogaster [14]. Whatever the precise mechanism, our results high-light the important influence of the late oocyte and zygote cytoplasm on the setting and maintenance of imprints [15].
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