We are interested in noncoding and epigenetic regulation of hematopoiesis and cancer. Currently, we are focusing on 1. Epigenetic mechanisms that control solid cancer and immune cell cross talks, 2. Noncoding RNAs in normal hematopoiesis and leukemia, 3. Finding novel functional noncoding sequences in the genome.
The completion of the human genome project leads to the realization that only a small percentage of our heritable DNA sequences encodes proteins. Instead of being “junk DNA”, a significant portion of the noncoding genome has functions, in the forms of non-coding RNAs, binding sites for protein factors or other functional sequences. These noncoding elements often cross-talk with epigenetic machinery to regulate cell fate and behavior.
In our laboratory, we use the amazing blood-forming system, or hematopoiesis, as a model to study the noncoding and epigenetic controls. In a normal adult human being, ~100 to 200 billion new blood cells are generated every day to replace similar numbers of existing blood cells. These mature blood cells originate from hematopoietic stem cells and exhibit vastly different forms, shapes and functions, regulating processes such as innate and adaptive immune responses, oxygen transport and coagulation. Mature blood cells, such as macrophages and neutrophils, can also be found in tumor tissues to control tumor cell behavior and anti-cancer immune responses. During aging, hematopoietic stem cells accumulate mutations in key tumor suppressor genes, most frequently those regulating DNA methylation. Mutant hematopoietic stem cells out-compete normal stem cells in a process termed clonal hematopoiesis. Clonal hematopoiesis is a near universal feature of human aging, increases the risk of diseases such as leukemia, and can have wider impacts on other aging-associated diseases such as vascular defects and solid cancer.
The fascinating biology discussed above raises a number of intriguing questions that we are addressing in our lab. What regulates the cross-talk between cancer cells and hematopoietic cells? What regulates the competition between clones of hematopoietic stem cells? What regulates the transformation of normal hematopoietic stem cell into malignant cells? How is the speed of hematopoietic regeneration regulated? What controls the form and function of mature blood cells?
Cell Differentiation; Hematologic Diseases; Hematopoiesis; Neoplasms; Cell Lineage