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Human Molecular Genetics Advance Access originally published online on December 22, 2004
Human Molecular Genetics 2005 14(4):493-502; doi:10.1093/hmg/ddi046
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Human Molecular Genetics, Vol. 14, No. 4 © Oxford University Press 2005; all rights reserved

Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells

Stefania Bottardi, Vincent Bourgoin, Natacha Pierre-Charles and Eric Milot*

Guy-Bernier Research Centre, Maisonneuve-Rosemont Hospital and Faculty of Medicine, University of Montreal, 5415 Boulevard l'Assomption, Montreal, Quebec, Canada H1T 2M4

Received October 6, 2004; Revised December 9, 2004; Accepted December 16, 2004

Abnormal epigenetic regulation of gene expression contributes significantly to a variety of human pathologies including cancer. Deletion of hypersensitive site 2 (HS2) at the human ß-globin locus control region can lead to abnormal epigenetic regulation of globin genes in transgenic mice. Here, two HS2-deleted transgenic mouse lines were used as model to demonstrate that heritable alteration of chromatin organization at the human ß-globin locus in multipotent hematopoietic progenitors contributes to the abnormal expression of the ß-globin gene in mature erythroid cells. This alteration is characterized by specific patterns of histone covalent modifications that are inherited during erythropoiesis and, moreover, is plastic because it can be reverted by transient treatment with the histone deacetylase inhibitor Trichostatin A. Altogether, our results indicate that aberrant epigenetic regulation can be detected and modified before tissue-specific gene transcription, a finding which may lead to novel strategies for the prevention of chromatin-related pathologies.

* To whom correspondence should be addressed. Tel: +1 5142523551; Fax: +1 5142523430; Email: eric.milot{at}hmr.qc.ca


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