title: 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.
authors.affiliation: Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Kaufman
authors.forename: Maya
authors.initials: M
authors.lastname: Heled
authors.forename: Jonathan
authors.initials: J
authors.lastname: Perk
authors.forename: Aharon
authors.initials: A
authors.lastname: Razin
authors.forename: Ruth
authors.initials: R
authors.lastname: Shemer
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019175:DNA Methylation / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D011218:Prader-Willi Syndrome / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes