Alteration of Hematopoietic Stem Cell Fates by Chromatin-Modifying Agents

Epigenetics is defined as modifications of the genome heritable during subsequent cell divisions that do not involve changes in the DNA sequence. DNA methylation plays a critical role in the regulation of genes which define tissue specific gene expression patterns, genome imprinting, and X-chromosome inactivation. DNA methylation has also been shown to be essential for normal mammalian development. DNA methylation and histone deacetylation are components of an epigenetic program that regulates gene expression pattern. Efforts devoted to maintaining the self-renewal and multilineage differentiation potential of human hematopoietic stem cells (HSC) and hematopoietic progenitor cells in vitro have met with limited success. The studies discussed here are based upon a hypothesis that conditions previously utilized for ex-vivo expansion of HSC result in the epigenetic silencing of genes required for HSC to undergo symmetrical cell divisions resulting in a progressive decline of primitive HSC function. Using pharmacological agents that interfere with DNA methylation and histone deacetylation, we and others have attempted to modify the fate of HSC in vitro. In this chapter, we review current advances in the use of chromatin-modifying agents to alter the fate of normal HSC. In particular, the effects of three drugs on normal HSC are described: a hypomethylating drug, 5-aza-2l-deoxycytidine; and two histone deacetylase inhibitors, trichostatin A and a drug traditionally used for treating epilepsy, valproic acid.