Human Molecular Genetics, 2001, Vol. 10, No. 15 1601-1609
© 2001 Oxford University Press
Distant cis-elements regulate imprinted expression of the mouse p57 Kip2 (Cdkn1c) gene: implications for the human disorder, Beckwith–Wiedemann syndrome
Wellcome/CRC Institute of Cancer and Developmental Biology, Tennis Court Road, Cambridge CB2 1QR, UK
Complex phenotypes and genotypes characterize the human disease, Beckwith–Wiedemann syndrome (BWS). Genetic and epigenetic mutations are found in five different genes which all lie within a 1 Mb imprinted domain on human chromosome 11p15. Only two of these genes, p57KIP2 (CDKN1C) and IGF2, are likely to be functionally involved in this disease. The presence of the additional mutations therefore suggests a role for the regulation of these two genes by distant cis-elements. The mouse Igf2 gene is regulated by enhancers and imprinting elements which lie >120 kb downstream of its promoter. Here we show that key elements for expression of the mouse p57Kip2 (Cdkn1c) gene also lie at a distance. Enhancers for expression within skeletal muscle and cartilage lie >25 kb downstream of the gene. In addition, we find no evidence for allele-specific expression of p57Kip2 (Cdkn1c) from our bacterial artificial chromosome transgenes that span 315 kb around the locus. This suggests that a key imprinting element for p57Kip2 (Cdkn1c) also lies at a distance. Therefore, BWS in humans may result from disruption of appropriate expression of the p57KIP2 (CDKN1C) gene through mutations that occur at a substantial distance from the gene.
+ To whom correspondence should be addressed. Tel: +44 1223 334138; Fax: +44 1223 334089; Email: rmj22@cus.cam.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Bilodeau, A. Roussel-Gervais, and J. Drouin Distinct Developmental Roles of Cell Cycle Inhibitors p57Kip2 and p27Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells Mol. Cell. Biol., April 1, 2009; 29(7): 1895 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. V. Fitzpatrick, E. M. Pugacheva, J.-Y. Shin, Z. Abdullaev, Y. Yang, K. Khatod, V. V. Lobanenkov, and M. J. Higgins Allele-Specific Binding of CTCF to the Multipartite Imprinting Control Region KvDMR1 Mol. Cell. Biol., April 1, 2007; 27(7): 2636 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rothschild, X. Zhao, A. Iavarone, and A. Lasorella E Proteins and Id2 Converge on p57Kip2 To Regulate Cell Cycle in Neural Cells. Mol. Cell. Biol., June 1, 2006; 26(11): 4351 - 4361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cerrato, A. Sparago, I. D. Matteo, X. Zou, W. Dean, H. Sasaki, P. Smith, R. Genesio, M. Bruggemann, W. Reik, et al. The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster Hum. Mol. Genet., February 15, 2005; 14(4): 503 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Paulsen, T. Khare, C. Burgard, S. Tierling, and J. Walter Evolution of the Beckwith-Wiedemann syndrome region in vertebrates Genome Res., January 1, 2005; 15(1): 146 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Scandura, P. Boccuni, J. Massague, and S. D. Nimer Transforming growth factor {beta}-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation PNAS, October 19, 2004; 101(42): 15231 - 15236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Murrell, S. Heeson, W. N. Cooper, E. Douglas, S. Apostolidou, G. E. Moore, E. R. Maher, and W. Reik An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype Hum. Mol. Genet., January 15, 2004; 13(2): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. REIK, A. MURRELL, A. LEWIS, K. MITSUYA, D. UMLAUF, W. DEAN, M. HIGGINS, and R. FEIL Chromosome Loops, Insulators, and Histone Methylation: New Insights into Regulation of Imprinting in Clusters Cold Spring Harb Symp Quant Biol, January 1, 2004; 69(0): 29 - 38. [Abstract] [PDF]
|
|
|
|
 |
|
 K. E. Bethin, Y. Nagai, R. Sladek, M. Asada, Y. Sadovsky, T. J. Hudson, and L. J. Muglia Microarray Analysis of Uterine Gene Expression in Mouse and Human Pregnancy Mol. Endocrinol., August 1, 2003; 17(8): 1454 - 1469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Weksberg, A. C. Smith, J. Squire, and P. Sadowski Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development Hum. Mol. Genet., April 2, 2003; 12(90001): R61 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mancini-DiNardo, S. J.S. Steele, R. S. Ingram, and S. M. Tilghman A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer Hum. Mol. Genet., February 1, 2003; 12(3): 283 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yatsuki, K. Joh, K. Higashimoto, H. Soejima, Y. Arai, Y. Wang, I. Hatada, Y. Obata, H. Morisaki, Z. Zhang, et al. Domain Regulation of Imprinting Cluster in Kip2/Lit1 Subdomain on Mouse Chromosome 7F4/F5: Large-Scale DNA Methylation Analysis Reveals That DMR-Lit1 Is a Putative Imprinting Control Region Genome Res., December 1, 2002; 12(12): 1860 - 1870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gong, X. W. Yang, C. Li, and N. Heintz Highly Efficient Modification of Bacterial Artificial Chromosomes (BACs) Using Novel Shuttle Vectors Containing the R6Kgamma Origin of Replication Genome Res., December 1, 2002; 12(12): 1992 - 1998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kanduri, G. Fitzpatrick, R. Mukhopadhyay, M. Kanduri, V. Lobanenkov, M. Higgins, and R. Ohlsson A Differentially Methylated Imprinting Control Region within the Kcnq1 Locus Harbors a Methylation-sensitive Chromatin Insulator J. Biol. Chem., May 10, 2002; 277(20): 18106 - 18110. [Abstract] [Full Text] [PDF]
|
|