Hematopoietic stem cell and transgenic animal model (Yan ZHANG)
Hematopoietic stem cells (HSCs) are a rare cell population that predominantly reside within adult bone marrow and are responsible for replenishing all hematopoietic and immune cell lineages throughout the lifetime of the animals. The development and differentiation of HSCs were precisely modulated by a broad range of mechanisms, including transcription factors, epigenetic factors, as well as signaling pathways. Alterations in these mechanisms could lead to dysfunctions in the development and differentiation of hematopoietic and immune cells. Define how these transcription factors, signaling pathways, and epigenetic factors contribute to the regulation of both normal and abnormal hematopoiesis will have profound implications not only for understanding of the basic molecular and cellular mechanisms that regulate normal hematopoiesis, but also for promoting clinical diagnosis and treatment of the hematopoietic and immune diseases.
Epigenetic regualtion of normal and malignant hematopoiesis.
We are currently focused on identifying and understanding the functions of histone-modifying enzymes in the control of self-renewal and differentiation regulation of HSCs, as well as their potential roles in leukemogenesis, by using gene-targeting mouse models. Our previous research indicated that Mixed Lineage Leukemia 5 (MLL5), one of the Trithorax group (TrxG) protein, plays an essential role in regulating HSCs self-renewal(BLOOD, 2009, Vol. 113: 1455-1463). Our recent research suggested that MLL5 controls G1-S phase cell cycle transition through binding to a cell cycle regulator Host Cell Factor 1 (HCF-1). This result provide a potential molecular mechanism that may help to explain how MLL5 contributes to HSCs self-renewal regulation (JBC, 2013, Vol: 288:17532-17543). We are now working toward understanding the roles of the other members of Trithorax group protein, as well as other histone-modifying enzymes, in both the normal and malignant hematopoiesis by using transgenic or knockout approaches.
Epigenetic regulation of lineage commitment and differentiation in the immune system.
The lineage commitment and differentiation of immune cells are regualted by transcriptional factors, cytokine signaling pathways, and epigenetic regulators. CD4+ T lympocytes play critical roles in orchestrating adaptive immune responses. Recent genome-wide analysis suggest that histone post-translational modifications involved in these processes, whereas their precise roles of the histone-modifying enzymes are still largely unclear. We are currently exploring the potential roles of histone modifying enzymes in the lineage commitment and differentiation of immune cells, particularly the na?ve CD4+ T lymphocytes, by using gene-targeted mouse models.
Mouse chromosome engineering for modeling human cancer.
chromosomal abnormalities occur frequently in human cancers, including the cancer in the hematopoietic and immune system. By using Cre-LoxP based techniques, we are generateing model the human cancer diseases in mouse with defined chromosomal alterations. One of our previous study generated a mouse model mimicking human 7q22 deletion leukemia(BLOOD, 2010, VOL: 115: 4524-4532). We are currently generating several leukemia models by using chromosomal engineering techinique. We designed a EGFP reporter–tracking strategy bywhich the leukemic cells with chromosomal translocation can be tracked during the induction of leukemogenesis. These new disease models will provide invaluable tools for the development of both diagnosis and treatment for human cancer.
Humanized Mouse Models for Studying Human Infectious Diseases and Cancer.
Humanized mouse models hold great promise for predictive in vivo preclinical drug testing. We are currently employing a combination of nuclease gene-knockout and transgenic approaches to generate immunocompromised mice bearing a mutated IL-2 receptor gamma chain (IL-2rγ) and several human cytokines transgenes permit the development of human hematopoietic/Immune system after human hematopoietic stem cells engraftment. These mice could be further improved by transplantation with a variety of human normal or cancer tissues to establish patients-derived xenograft cancer models.