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Nucleic Acids Research Advance Access published online on September 18, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp749
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

Demonstration of all-or-none loss of imprinting in mRNA expression in single cells

Andreas I. Diplas1, Jianzhong Hu2, Men-Jean Lee3, Yula Y. Ma3, Yin L. Lee1, Luca Lambertini1, Jia Chen1,4,5 and James G. Wetmur2,6,*

1Department of Community and Preventive Medicine, 2Department of Microbiology, 3Department of Obstetrics, Gynecology, and Reproductive Science, 4Department of Pediatrics, 5Department of Oncological Science and 6Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA

*To whom correspondence should be addressed. Tel: 212 241 7685; Fax: 212 534 1684; Email: james.wetmur{at}mssm.edu

Received July 2, 2009. Revised August 25, 2009. Accepted August 26, 2009.

Loss of imprinting (LOI) is the reactivation of the silenced allele of an imprinted gene, leading to perturbation of monoallelic expression. We tested the hypothesis that LOI of PLAGL1, a representative maternally imprinted gene, occurs through an all-or-none process leading to a mixture of fully imprinted and nonimprinted cells. Herein using a quantitative RT-PCR-based experimental approach, we measured LOI at the single cell level in human trophoblasts and demonstrated a broad distribution of LOI among cells exhibiting LOI, with the mean centered at ~100% LOI. There was a significant (P < 0.01) increase in expression after 2 days of 5-aza-2'-deoxycytidine (AZA) treatment and a significant (P < 0.01) increase in LOI after both 1 and 2 days of AZA treatment, while the distribution remained broad and centered at ~100% LOI. We propose a transcriptional pulsing model to show that the broadness of the distribution reflects the stochastic nature of expression between the two alleles in each cell. The mean of the distribution of LOI in the cells is consistent with our hypothesis that LOI occurs by an all-or-none process. All-or-none LOI could lead to a second distinct cell population that may have a selective advantage, leading to variation of LOI in normal tissues, such as the placenta, or in neoplastic cells.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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