Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells

Abnormal epigenetic regulation of gene expression contributes significantly to a variety of human patho-logies including cancer. Deletion of hypersensitive site 2 (HS2) at the human b-globin locus control region can lead to abnormal epigenetic regulation of globin genes in transgenic mice. Here, two HS2-deleted trans-genic mouse lines were used as model to demonstrate that heritable alteration of chromatin organization at the human b-globin locus in multipotent hematopoietic progenitors contributes to the abnormal expression of the b-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 tran-scription, a finding which may lead to novel strategies for the prevention of chromatin-related pathologies