Credentials: Medical Sciences Department
Position title: Epigenetic regulation, hematopoiesis, mouse models
4470 Veterinary Medicine Building
2015 Linden Dr
Madison, WI 53706
Cancer Biology; Transcriptional Mechanisms
It is well known that Hematopoietic Stem Cells (HSCs) are undifferentiated, self-renewing, pluripotent cells that have the capacity to differentiate into all mature lineage-specific cells in adult blood. In adult humans, bone marrow produces more than one million mature blood cells per second. If the correct balance between HSC self-renewal and differentiation is not maintained, hematopoietic cancers such as leukemia and lymphoma can develop. Further, HSCs can be a powerful therapeutic tool. Approximately 20,000 patients receive HSC transplants per year in the U.S.; however, the efficacy of HSC transplantation, as well as other clinical applications for HSCs, are limited due to challenges in maintaining and/or expanding HSC cultures ex vivo. As the genetic and epigenetic mechanisms that regulate proliferation, differentiation and self-renewal in HSCs are incompletely defined, my laboratory is currently investing significant effort to address questions and knowledge gaps in this important research area.
The balance between HSC self-renewal and differentiation is maintained by a number of mechanisms, including crosstalk between gene transactivation/repression and extrinsic cell signaling. Based on prior discoveries in my laboratory, we have focused on Yin Yang 1 (YY1), and its important biological function as a regulator of HSC self-renewal and quiescence. YY1 is a ubiquitous transcription factor and mammalian Polycomb Group Protein (PcG) with important roles in embryonic development, lineage differentiation and cell proliferation. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Many questions remain unanswered regarding how PcG proteins achieve cellspecificity. Our work demonstrated that a conditional knockout of Yy1 in HSCs decreased HSC long-term repopulating activity, while ectopic expression of YY1 expanded HSCs. Although the YY1 PcG domain is required for Igk chain rearrangement in B cells, the YY1 mutant lacking the PcG domain retained the capacity to stimulate HSC self-renewal. YY1 deficiency deregulated the genetic network governing HSC cell proliferation, impaired stem cell factor/c-Kit signaling, and disrupted mechanisms that confer HSC quiescence. These results reveal how YY1, a ubiquitouslyexpressed transcriptional repressor, mediates lineage-specific functions to control adult hematopoiesis.