Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells.
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 beta-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 beta-globin locus in multipotent hematopoietic progenitors contributes to the abnormal expression of the beta-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.
Bottardi
Stefania
S
Guy-Bernier Research Centre, Maisonneuve-Rosemont Hospital and Faculty of Medicine, University of Montreal, 5415 Boulevard l'Assomption, Montreal, Quebec, Canada H1T 2M4.
Bourgoin
Vincent
V
Pierre-Charles
Natacha
N
Milot
Eric
E
D000107:Acetylation; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism* / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004920:Erythropoiesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005914:Globins / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C012589:trichostatin A; D005914:Globins; D019009:Proto-Oncogene Proteins c-kit