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Originally published in Science Express on 22 November 2001
Science 21 December 2001:
Vol. 294. no. 5551, pp. 2536 - 2539
DOI: 10.1126/science.1065848
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Reports

Dnmt3L and the Establishment of Maternal Genomic Imprints

Déborah Bourc'his,1 Guo-Liang Xu,1* Chyuan-Sheng Lin,2 Brooke Bollman,1dagger Timothy H. Bestor1ddagger

Complementary sets of genes are epigenetically silenced in male and female gametes in a process termed genomic imprinting. The Dnmt3L gene is expressed during gametogenesis at stages where genomic imprints are established. Targeted disruption of Dnmt3L caused azoospermia in homozygous males, and heterozygous progeny of homozygous females died before midgestation. Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. The defect was specific to imprinted regions, and global genome methylation levels were not affected. Lack of maternal methylation imprints in heterozygous embryos derived from homozygous mutant oocytes caused biallelic expression of genes that are normally expressed only from the allele of paternal origin. The key catalytic motifs characteristic of DNA cytosine methyltransferases have been lost from Dnmt3L, and the protein is more likely to act as a regulator of imprint establishment than as a DNA methyltransferase.

1 Department of Genetics and Development,
2 Transgenic Animal Facility, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
*   Present address: Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.

dagger    Present address: Department of Biological Sciences, Dartmouth College, Hanover, NH, USA.

ddagger    To whom correspondence should be addressed. E-mail: thb12{at}columbia.edu

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Genomic Imprinting: Antagonistic Mechanisms in the Germ Line and Early Embryo.
A.M. FEDORIW, N.I. ENGEL, and M.S. BARTOLOMEI (2004)
Cold Spring Harb Symp Quant Biol 69, 39-46
   Abstract »    PDF »
Role of De Novo DNA Methyltransferases in Initiation of Genomic Imprinting and X-Chromosome Inactivation.
M. KANEDA, T. SADO, K. HATA, M. OKANO, N. TSUJIMOTO, E. LI, and H. SASAKI (2004)
Cold Spring Harb Symp Quant Biol 69, 125-130
   Abstract »    PDF »
Transposon Silencing and Imprint Establishment in Mammalian Germ Cells.
T.H. BESTOR and D. BOURC'HIS (2004)
Cold Spring Harb Symp Quant Biol 69, 381-388
   Abstract »    PDF »
Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology.
D. Lucifero, J.R. Chaillet, and J. M. Trasler (2004)
Hum. Reprod. Update 10, 3-18
   Abstract »    Full Text »    PDF »
Role of the DNA Methyltransferase Variant DNMT3b3 in DNA Methylation.
D. J. Weisenberger, M. Velicescu, J. C. Cheng, F. A. Gonzales, G. Liang, and P. A. Jones (2004)
Mol. Cancer Res. 2, 62-72
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)