Protein-binding elements establish in the oocyte the primary imprint of the Prader-Willi/Angelman syndromes domain

Abstract

Imprinting of the PWS/AS 2.4 Mb domain in the human is controlled by a paternally active imprinting center (PWS-IC). PWS-IC on the maternal allele is methylated and inactivated by an 880-bp sequence (AS-IC) located 30 kb upstream. In this communication, we report the identification of 7 cis acting elements within AS-IC. The elements: DMR, DNS, 2 OCTA sequences, SOX, E1, and E2 bind specific proteins that form at least 2 protein complexes. Using variants of an imprinted transgene, mutated at the elements each at a time, we show that (i) all 7 elements are involved in the methylation and inactivation of the maternal PWS-IC; (ii) the OCTA and SOX elements that bind a protein complex, and the E1 and E2 elements, function in establishing the primary imprint that constitutes an active and unmethylated AS-IC in the oocyte; (iii) DNS and DMR bind a multiprotein complex that may facilitate interaction between AS-IC and PWS-IC, mediating the inactivation in cis of PWS-IC; and (iv) all 7 elements participate in maintaining an unmethylated PWS-IC in the oocyte, which is essential for its maternal methylation later in development. Altogether, the above observations imply that the cis acting elements on AS-IC display diverse functions in establishing the imprints at both AS-IC and PWS-IC in the oocyte. A postulated epigenetic mark imprints the PWS-IC in the oocyte and maintains its inactive status during development before it is translated into maternal methylation.cis elements ͉ DNA methylation ͉ imprinting ͉ protein factors

Genomic imprinting in germ cells: imprints are under control

“…Similarly, failure to establish the Snrpn ICR methylation imprint in Zfp57K/K eggs could be partially rescued by the paternally derived ZFP57 at post-implantation stages ). These observations, especially at the Snrpn ICR, are consistent with studies that report that methylation at the SNRPN ICR in humans might occur after fertilisation (El-Maarri et al 2001, Kaufman et al 2009note, however, that Geuns et al (2003) found that the human SNRPN ICR is methylated already in oocytes).…”

Identification of a DNA methylation-independent imprinting control region at the Arabidopsis MEDEA locus

“…A related situation may occur in the mouse Prader-Willi/Angelman region showing a complex imprinting control involving several cis-acting elements, one of which is not differentially methylated but is required to establish parental imprints at other sites (Kaufman et al 2009). Moreover, it was recently shown that in macaques, some ICRs that acquire a germline DNA methylation imprint in mice are not methylated in the germline and acquire a differential methylation mark only post-fertilization (A FergusonSmith, pers.…”

Genomisches Imprinting und Imprintingfehler

“…Das erhöhte Risiko konnte den Allen zweier Polymorphismen zugeordnet werden. Wahrscheinlich enthält das IC eine Bindungsstelle für einen trans-aktiven Faktor, der für die Etablierung des maternalen Imprints eine Rolle spielt und vermutlich mit unterschiedlicher Effizienz an die verschiedenen Allele bindet [21]. Darin könnte ein erhöhtes Risiko dafür liegen, dass das maternale Imprint nicht oder nicht vollstän-dig etabliert wird.…”