Human Molecular Genetics Advance Access published online on March 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl041
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1 Institute of Reproductive and Developmental Biology, Imperial College London, W12 ONN, UK
* To whom correspondence should be addressed. Genomic imprinting is limited to a subset of genes that play critical roles in fetal growth, development and behaviour. One of the most studied imprinted genes encodes insulin-like growth factor 2, and aberrant imprinting and DNA methylation of this gene is associated with the growth disorders Beckwith-Wiedemann and Silver-Russell syndromes and many human cancers. Specific isoforms of this gene have been shown to be essential for normal placental function, since mice carrying paternal null alleles for the Igf2-P0 transcript are growth restricted at birth. We report here the identification of three novel human transcripts from the IGF2 locus. One is equivalent to the mouse Igf2-P0 transcript, while the two others (INSIGF long and short) originate from the upstream INS gene that alternatively splices to downstream IGF2 exons. In order to elucidate the molecular mechanisms involved in the complex imprinting of these novel IGF2 transcripts, both the allele-specific expression and methylation for all the IGF2 promoters including P0 and the INSIGF transcripts were analysed in human tissues. Similar to the mouse, the human IGF2-P0 transcript is paternally expressed, however, its expression is not limited to placenta. This expression correlates with tissue specific promoter methylation on the maternal allele. The two novel INSIGF transcripts reported here use the INS promoter and show highly restricted tissue expression profiles including the pancreas. As previously reported for INS in the yolk sac, we demonstrate complex, tissue-specific imprinting of these transcripts. The finding of additional transcripts within this locus will have important implications for IGF2 regulation in both cancer and metabolism.
Received December 22, 2005
Revised February 14, 2006
Accepted February 14, 2006
Article
Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human
D. Monk 1 *,
R. Sanches 2,
P. Arnaud 3,
S. Apostolidou 1,
F.A. Hills 4,
S. Abu-Amero 1,
A. Murrell 5,
H. Friess 6,
W. Reik 2,
P. Stanier 1,
M. Constância 2,
and
G.E. Moore 1
2 Laboratory for Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, CB2 4AT, UK
3 Institute of Molecular Genetics, CNRS, UMR-5535 and University of Montpellier II, 1919 Route de Mende, 34090 Montpellier, France
4 School of Health and Social Sciences, Middlesex University, Enfield, EN3 4SA, UK
5 Department of Oncology, Cambridge University, MRC-Hutchison Centre, Cambridge, CB2 2XZ
6 Department of General Surgery, University of Heidelberg, Heidelberg, Germany
D. Monk, E-mail: d.monk{at}imperial.ac.uk
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