Chromatin Structure and Stem Cell Biology
The blood is a living tissue composed of billions of short-lived red blood cells, white blood cells and platelets that must be constantly replenished by a rare population of self-renewing hematopoietic stem cells (HSCs). Dysregulation of this fundamental process -known as hemopoiesis- causes a variety of hematological malignancies and disorders in humans. Leukemia, for example, can be viewed as a newly formed, abnormal hematopoietic tissue initiated by a rare population of leukemic stem cells (LSCs) that undergoes an abnormal and aberrantly regulated process of organogenesis analogous to that of normal hemopoiesis. The recent demonstration that human HSCs can be expanded in vitro has fueled the hope that mobilization of these cells might provide an alternative therapy for the treatment of hematological disorders such as anemia and thalassemia. Before the full potential of HSCs can be realized, we need to learn what controls their self-renewal and proliferative capacities, as well as the various pathways of differentiation available to their daughter cells.
One determinant of cell fate are patterns of chromatinization of genetic loci that are established during differentiation, and that limit the possible outcomes of general signaling events to the activation of lineage-specific genes. In the past few years, great effort has been devoted to the identification of post-translational histone modifications involved in gene regulation. These epigenetic marks work alone or in combinatorial fashion to constitute a “histone code” that regulate chromatin structure and function. Our work now suggests that combinatorially assembled chromatin remodelers of the SWI/SNF family could act in an equally complex manner to regulate transcriptional programs of gene expression during cellular differentiation.
Strikingly, our most recent studies demonstrate that some subunits of ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes are essential for HSC function, while others are required later in the hemopoietic hierarchy for the development of specific lineages (i.e. lymphoid, erythroid or granulocytic-specific functions). We are currently entertaining the possibility that combinatorial assembly of alternative families of subunits confers functional specificity to BAF complexes by allowing the recognition of distinct gene targets during hematopoietic differentiation.
Current investigation involves a combination of modern proteomics, molecular genetics, cellular and biochemical methods.