Research

The long-term goal of our lab is to understand the systemic network governed by epigenetic factors in stem cells. We want to dissect the mechanisms that makes a stem cell a stem cell (cell identity), maintains as a stem cell (stemness) or goes to a specific lineage (cell fate determination). We adopted a well established system to dissect the interactive network controlling adult stem cells and cancer stem cells, and differentiated blood cells functions from the angle of non-coding RNAs.

Several major direction that we are currently interested in are:

The regulation of microRNAs in hematopoietic stem cell function
Mechanism of microRNAs in macrophage activation and obesity induced cardiac vascular diseases
microRNAs act as oncogenes or tumor suppressors in leukemogenesis and progression
Rheostatic regulation of microRNs in lymphocytes formation and function

The regulation of microRNAs in hematopoietic stem cell function

Limited self-renewal and differentiation of hematopoietic stem cells (HSCs) and their progenies rely on a well-orchestrated regulatory network, mainly comprising transcription factors, cytokines and their receptors mediated signaling pathways, and a group of newly discovered microRNAs (miRNAs). Even though there are experimental evidences suggesting the important roles played by miRNAs in this network, the detailed picture is largely unknown. Our lab is interested in investigating the regulation network governed by miRNAs in hematopoiesis, in particular lymphopoiesis. In addition, abnormal miRNA expression, along with gene mutations, can transform hematopoietic stem cells and progenitor cells to "indefinite self-renewal" cancer stem cells, thus lead to hematopoietic malignancies, such as leukemia and lymphoma.

microRNAs regulated macrophage function in obesity induced adipose inflammation

Leukocytes are not only crucial cells for immune responses, but also pivotal in regulators for other tissues' function. A new dimension of our research is to investigate the interactions between leukocytes and connective tissue cells that composite the micro-environment after their emigration. Cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) are the leading causes of mortality and morbidity in the United States. Among various CVDs, atherosclerosis associated complications account for more than half of the year mortality. Meanwhile, it is well accepted obesity and its associated type 2 diabetes mellitus (T2DM) are major contributors for the high incidence of CVD, including atherosclerosis. Growing evidences indicated the pivotal role of macrophage mediated inflammation is one of the crucial factors for the pathogenesis of both atherosclerosis and T2DM. However, the detailed picture of how macrophage function remains vague. Our long-term goal is to elucidate the underlying mechanism of CVD risk and providing crucial information for new therapeutic strategy development for obesity induced CVD.

microRNAs act as oncogenes or tumor suppressors in leukemogenesis and progression

Leukemia is cancer that affect blood cells formation and bone marrow function. In 2011, more than 44,000 cases were diagnosed and greater than 21,000 people died of leukemia. Our research goal is to reveal the mechanism of leukemogenesis by identifying oncogenes, tumor suppressors and dissecting their mediated networks that govern cancer transformation. We use epigenetic tools to investigate this process, including DNA and Chromosomal modification, as well as non-coding RNAs. Similar to key transcription factors, several microRNAs that are crucial regulators of blood cell formation, i. e hematopoietic stem cell function and differentiation, are also important regulators for leukemogenesis and progress. Profiling studies identified abnormal expression patterns of microRNAs that are associated with various types of leukemias. However, only a few of them have been characterized for their exact role and how they function in this context. We recently identified several microRNAs that are actively involved in leukemogenesis and progression by modulating multiple target genes mediated the networks that are governing leukemic stem cell identity and function. To elucidate the mechanism of such regulation will provide new and important insights on systemic regulation of normal and cancerous stem cell development.

Rheostatic regulation of microRNs in lymphocytes formation and function

Tissue specific and cell lineage specifc microRNAs are also crucial regulators for cell development. Our previous publication indicated that (PNAS, 2007) miR-150, a conserved microRNA that highly expressed in lymphocytes with developmental pattern also play important role for B cell formation. miR-150, is mainly expressed in the lymph nodes and spleen and is highly up-regulated during the development of mature T and B cells; expression of miR-150 is sharply up-regulated at the immature B cell stage. Overexpression of miR-150 in hematopoietic stem cells, followed by bone marrow transplantation, had little effect on the formation of either mature CD8+ and CD4+ positive T cells or granulocytes or macrophages, but the formation of mature B cells was greatly impaired. Furthermore, premature expression of miR-150 blocked the transition from the pro-B to the pre-B stage. Our results indicate that miR-150 most likely down-regulates mRNAs that are important for pre- and pro-B cell formation or function, and its ectopic expression in these cells blocks further development of B cells. Using this microRNA model, we are investigating the early checkpoint events regulating networks that are affected by this microRNA.