Epigenetics and Stem Cells
Tony Krumm
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.
Daniel G. Miller (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.
