Human Molecular Genetics Advance Access originally published online on February 12, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2004, Vol. 13, No. 7 751-762
DOI: 10.1093/hmg/ddh085
Control elements within the PWS/AS imprinting box and their function in the imprinting process
Department of Cellular Biochemistry and Human Genetics, The Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel
Received December 15, 2003; Accepted February 4, 2004
A cluster of imprinted genes on human chromosome 15q11–q13 (the PWS/AS domain) and its ortholog on mouse chromosome 7c is believed to be regulated by an imprinting control center. Although minideletions in this region in Angelman syndrome (AS) and Prader–Willi syndrome (PWS) patients revealed that two elements, shortest deletion regions of overlap in AS families and PWS families (AS–SRO and PWS–SRO), respectively, constitute the IC, the molecular mechanism that governs this regional control remains obscure. To understand how this imprinting center works, a mouse model was sought. The striking similarity between the human and mouse sequences allowed the generation of a minitransgene (AS–SMP) composed of AS–SRO and the Snrpn minimal promoter (SMP) the mouse ortholog of PWS–SRO. This minitransgene carries out, in a highly reliable and reproducible manner, all steps of the imprinting process. In an attempt to decipher the molecular mechanism of the imprinting process, we generated and tested for imprinting five minitransgenes based on AS–SMP, in which various parts of the 160 bp SMP were deleted. These experiments revealed a set of five cis elements that carry out the various steps of the imprinting process. This set includes: (i) two copies of a de novo methylation signal (DNS) that establish the maternal imprint during oogenesis; (ii) an allele discrimination signal that establishes the paternal imprint; and (iii) two elements that act together to maintain the paternal imprint. Two functionally redundant sets of the five elements were found on the respective endogenous mouse sequence explaining the previously published contradictory results of targeted deletion experiments. Together with the fact that all five elements bind specific proteins that are presumably the factors acting in trans in the imprinting process, our observations set the stage for a comprehensive study of the molecular mechanism involved in the control of the imprinting process.
* To whom correspondence should be addressed. Tel: +972 26758172; Fax: +972 26415848; Email: razina{at}md2.huji.ac.il
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Kaufman, M. Heled, J. Perk, A. Razin, and R. Shemer Protein-binding elements establish in the oocyte the primary imprint of the Prader-Willi/Angelman syndromes domain PNAS, June 23, 2009; 106(25): 10242 - 10247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Goodin, M. Chen, E. Lose, F. M. Mikhail, and B. R. Korf Advances in Genetic Testing and Applications in Newborn Medicine NeoReviews, July 1, 2008; 9(7): e282 - e290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Holmes, Y. Chang, and P. D. Soloway Timing and Sequence Requirements Defined for Embryonic Maintenance of Imprinted DNA Methylation at Rasgrf1 Mol. Cell. Biol., December 15, 2006; 26(24): 9564 - 9570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Federman The Biology of Human Sex Differences N. Engl. J. Med., April 6, 2006; 354(14): 1507 - 1514. [Full Text] [PDF]
|
|
|
|
|
|
B. Yoon, H. Herman, B. Hu, Y. J. Park, A. Lindroth, A. Bell, A. G. West, Y. Chang, A. Stablewski, J. C. Piel, et al. Rasgrf1 Imprinting Is Regulated by a CTCF-Dependent Methylation-Sensitive Enhancer Blocker Mol. Cell. Biol., December 15, 2005; 25(24): 11184 - 11190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rodriguez-Jato, R. D. Nicholls, D. J. Driscoll, and T. P. Yang Characterization of cis- and trans-acting elements in the imprinted human SNURF-SNRPN locus Nucleic Acids Res., August 22, 2005; 33(15): 4740 - 4753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kantor, Y. Kaufman, K. Makedonski, A. Razin, and R. Shemer Establishing the epigenetic status of the Prader-Willi/Angelman imprinting center in the gametes and embryo Hum. Mol. Genet., November 15, 2004; 13(22): 2767 - 2779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Landers, D. L. Bancescu, E. Le Meur, C. Rougeulle, H. Glatt-Deeley, C. Brannan, F. Muscatelli, and M. Lalande Regulation of the large (~1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn Nucleic Acids Res., June 29, 2004; 32(11): 3480 - 3492. [Abstract] [Full Text] [PDF]
|
|