Lymphocyte development represents a unique and practical model for genetic analysis of gene regulation in mammals. In contrast to many embryonic cell types, lineage specification, differentiation, and expansion of B- and T-lymphocytes occur constantly throughout a human life. These dynamic processes have to be tightly regulated in order to generate and maintain the immune system; otherwise lymphopenia, lymphoma, leukemia, or other lymphoid diseases may occur.
Recent studies have demonstrated that basic-helix-loop-helix (bHLH) proteins encoded by the E2A and HEB genes play major roles in lymphocyte development. Mutations in the E2A gene and aberrant expression of other related bHLH genes are major genetic factors in human acute lymphocytic leukemias. Evidence indicates that these bHLH proteins activate gene expression by directly binding to E-box sites present in many lymphocyte specific genes. We have shown that a disruption of E2A or HEB in mice leads to early arrests in B- or T- cell development, respectively. However, it is not fully understood how mechanistically E2A and HEB control lymphocyte development.
The main focus of the lab is to understand gene regulation mediated by these bHLH and related regulatory proteins during normal and abnormal lymphocyte development. Two types of genetic approaches are used: gene targeting and chemical mutagenesis. Various gene targeting techniques (including conventional knockout, knockin, and conditional knockout) are used to define gene functions and to create in vivo and in vitro models for dissecting gene functions. ENU-mutagenesis is carried out to genetically identify E2A modifiers. Mutations capable of enhancing E2A induced phenotypes will be analyzed at genetic and biochemical levels and eventually isolated through positional cloning.
The long term goal is to gain better understanding of the bHLH mediated molecular pathways underlying lymphocyte development and to provide new therapeutic strategies for lymphoid diseases.
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