Research Seminar: Gene regulatory mechanisms in the launch process of T cell development – Dr. Ellen Rothenberg

Research Seminar: Gene regulatory mechanisms in the launch process of T cell development – Dr. Ellen Rothenburg </font color>

Location:
Lecture Theatre B1001, Gordon B. Shrum Building – 6088 University Boulevard, Vancouver BC

Unlike the great majority of hematopoietic cell types, T cells do not develop in the bone marrow, but from bone marrow-derived precursors that have migrated to the thymus.   This has led to some controversy about how T-cell precursors truly emerge from the stem and multipotent progenitor cell programs that give rise to all other blood cells.  We have used a variety of approaches to trace the earliest steps of the T cell developmental pathway and the gene regulatory networks and transcription factor activity relationships that start the T cell program.

T cell development is known to be initiated by Notch-Delta-like 4 signaling in the thymic environment and guided by the actions of transcription factors that include TCF1 (Tcf7 gene product), GATA3, BCL11B, RUNX1 and RUNX3, E2A and HEB, IKAROS, and MYB.  Most of these transcription factors are critical both at the beginning of T cell development and in repeated roles at later T-cell lineage choices, for example, controlling the CD4/CD8 developmental choice.  However, the ability to generate T cells also depends on progenitor-cell associated transcription factors that play little or no role in mature T cells and which may be expressed in mature cells of non-T lineages only, such as PU.1 (Spi1 gene product), BCL11A, LYL1, and HHEX.  Our group has shown that in the earliest stages of T cell development there is overlapping expression of T-lineage biased factors and these progenitor-associated factors, and that although they are all required at some point to make T cells, they cross-regulate each other in a dynamic, competitive gene regulatory network within the same cell nuclei. Perturbation analyses and molecular genomic analyses show that the antagonism between these two groups of transcription factors controls the speed of initiation of the T cell program in individual cells.  I will describe how this works and further explore the role of this opposition in differences between postnatal and fetal T cell development, when differentiation occurs much faster but with more production of gamma delta T and innate lymphoid cells.

Dr. Ellen Rothenberg’s Biography:

Ellen V. Rothenberg, Ph.D., the Edward B. Lewis Professor of Biology at Caltech, studies molecular mechanisms underlying lymphocyte development. She graduated from Harvard University and received her Ph.D. from MIT. After a Jane Coffin Childs Postdoctoral Fellowship at Memorial Sloan-Kettering Cancer Center, she took a faculty position at the Salk Institute for Biological Studies, then joined the Caltech faculty in 1982. She has served on external advisory boards for academic research institutes in multiple countries, chaired the scientific advisory boards for the Max-Planck Institute for Immunobiology and Epigenetics and the Institute for Systems Biology, has taught in international advanced courses in immunology, developmental biology and systems biology, and has co-organized multiple immunology conferences in the US, UK, and Greece. She has been awarded the Richard P. Feynman Prize for Excellence in Teaching (Caltech) and selected as a Distinguished Fellow of the American Association of Immunologists (inaugural class), and she has been elected to the American Association for the Advancement of Science, the American Academy of Arts and Sciences, and the National Academy of Sciences (USA). Her group studies gene regulation and development of T lymphocytes, gene networks controlling hematopoietic cell fates, and mechanisms underlying the dynamics of single-cell developmental decisions.