Epigenetics and Stem Cells
Karol Bomsztyk, MD (Medicine)
Understanding the processes that signal gene expression is critically important for using stem cells in the treatment of disease. These intracellular processes include many factors that are organized into signaling cascades that regulate genes in the chromatin environment, or the epigenome. To better define these mechanisms our laboratory has been developing advanced epigenetic technologies and computational tools. Our and other member laboratories of the UW Medicine Institute for Stem Cell and Regenerative Medicine are already using these methods to better understand and treat cancer, diabetes, kidney, heart and other diseases where stem cell biology holds great promises.
Christine Disteche (Pathology)
Research in my lab focuses on the regulation of the mammalian X chromosome.
Zhijun Duan, PhD (Hematology)
The focus of our research is on the relationship between the form and function of human genomes during development and tumorigenesis.
Tony Krumm, PhD (Radiation Oncology)
The differentiation of stem cells to a variety of cell types is controlled by genetic and epigenetic mechanisms. There is compelling evidence that epigenetic alterations play a critical role in the pathogenesis of cancer, diabetes, and heart disease. This lab is studying chromatin structure and genome-wide distribution of factors required for epigenetic control of gene expression and genomic imprinting. Our studies include research on chromosomal elements that shield transcription domains from the advance of silencing heterochromatic structures into the gene domain. This barrier function is often accompanied by an insulator activity that prevents inappropriate gene activation through adjacent enhancer elements. Together, these elements function as gatekeepers that either permit or prevent access of regulatory signals to transcription domains. The ability to block transcriptional enhancers is also an important component of monoallelic gene expression at some imprinted gene loci. We have developed an experimental strategy to identify genes transcribed on either the maternal or paternal allele across the human genome. Generating a catalogue of epigenetic alterations will provide molecular signatures that are essential to the development of novel tools in the diagnosis and therapy of human disease.
David L. Mack (Rehabilitation Medicine)
The Mack laboratory combines stem cell and gene therapies to develop new treatments for neuromuscular diseases. Induced pluripotent stem cell technology is used to generate patient-specific stem cells that can undergo directed-differentiation to multiple lineages in culture. Three-dimensional scaffolds are also being employed to further differentiate each cell type into their more mature form. This so called “disease-in-a-dish” approach will enable us to study disease mechanisms, and to create novel drug discovery platforms. Drugs identified in this way are likely to work in the patient since the patient’s own cells were used as the screening tool. Diseases being explored include Duchenne muscular dystrophy, X-linked myotubular myopathy and autistic syndrome disorder.
Dr. Mack is a classically trained geneticist with expertise in developmental and stem cell biology. During his postdoctoral fellowship at the National Cancer Institute, he studied how the stem cell microenvironment controls cell fate during mammary gland development. His recent contributions to the field of regenerative medicine center on the interplay between a cell’s genetic program and it microenvironment during lineage commitment.
Daniel G. Miller, MD, PhD (Pediatrics)
Dr. Miller and members of his research group utilize induced pluripotent stem cells (IPSc) made from the skin cells of individuals with Facioscapulohumeral Muscular Dystrophy (FSHD) to understand the etiology of this debilitating condition. The hypothesis is that FSHD is caused by a defect in muscle development and/or maintenance so studying differences between control and patient embryonic cells as they differentiate to form muscle may reveal key mechanisms of disease pathology. Dr. Miller is also interested in treatment strategies for genetic conditions so members of his research group use vectors based on Adeno-Associated Virus (AAV) to perform gene targeting in primary human cells. This approach is currently being applied to keratinocytes from patients affected with a skin blistering condition called Epidermolysis Bullosa. The molecular consequence of disease-causing mutations can also be studied by creating the same mutations in primary human cells, or correcting mutations in cells from affected patients.
Dr. Miller also sees patients with genetic conditions in the pediatric medical genetics clinic at Children’s Hospital.
Ray Monnat, PhD (Pathology and Genome Sciences)
Our research focuses on human RecQ helicase deficiency syndromes such as Werner syndrome; high resolution analyses of DNA replication dynamics; and the engineering of homing endonucleases for targeted gene modification or repair in human and other animal cells.
Thalia Papayannopoulou, PhD (Hematology, Medicine)
Dr. Thalia Papayannopoulou's research program aims to understand the mechanisms whereby hematopoietic stem cells home to bone marrow following transplantation, and how they traffic between the marrow and the blood stream under normal and perturbed hematopoiesis. A particular focus is on the characterization of the hematopoietic stem cell niche. In addition, Papayannopoulou lab studies erythroid cell development during the embryonic, fetal and adult stages of development.
David W. Raible, PhD (Biological Structure)
We are interested in the development of the peripheral nervous system using zebrafish as a model. Current research focuses on two areas: sensory neurons derived from neural crest and the mechanosensory lateral line system.
Thomas N. Wight, PhD (Benaroya Research Institute)
This investigator leads a research program focused on the role that the extracellular matrix molecules, proteoglycans and hyaluronan, play in regulating vascular cell type and the regulation of extracellular matrix assembly. These pathways are fundamental to understanding the growth of new blood vessels in different tissues of the body, and have potential for direct tissue regeneration applications through the use of proteoglycan genes to bioengineer vascular tissue.