New Mechanisms Controlling Gene Network Dynamics for T-cell Specification and Commitment

Friday, February 23, 2018 -
2:00pm to 3:00pm
The FUNG Auditorium
Ellen Rothenberg

Albert Billings Ruddock Professor of Biology

Division of Biology and Biological Engineering

California Institute of Technology

New Mechanisms Controlling Gene Network Dynamics for T-cell Specification and Commitment

Development of pluripotent cells into differentiated derivatives is a process that depends on an ordered cascade of transcriptional regulatory changes, each step contingent upon those that precede it.  At each of these regulatory steps, transcription factors already present in the cell combine to activate transcription at new loci and/or downregulate transcription at previously active loci. To model the dynamics of these processes, it is clearly important to know the transcriptional requirements for the genes to be controlled at each step and the availabilities of the factors that provide these inputs. However, there are also hidden assumptions about how transcription factors “ought to” work that affect the success of these models. One set of assumptions concerns the basis for combinatorial action of transcription factors and the extent to which this reflects simultaneous or even cooperative binding to the DNA.  Another set of assumptions concerns the impact of prior developmental states of a given cell on the current accessibility of target sites in its DNA, via chromatin modifications (“epigenetic states”).  How do transcription factors really affect each other’s activity at given genomic sites? And how much does prior “epigenetic state” affect the action of transcription factors on a given target?   This talk provides new answers to these questions, based on exploiting a particularly well-defined developmental model system, namely the emergence of newly committed T-lymphocyte precursors from multipotent progenitors in the mouse thymus. This is a biologically rich process that involves scores of transcription factors and winnows down the developmental options available to the precursors over a span of 10-15 cell cycles. However, the deep knowledge available about this process and the system’s accessibility to perturbation make it highly tractable for addressing these basic questions of developmental genomics. The talk will present recent insights about how transcription factors interact with each other and with the epigenetic states in the precursor cells to bring about highly regulated but essentially irreversible developmental change.

Ellen Rothenberg is the Albert Billings Ruddock Professor of Biology at the California Institute of Technology, Pasadena, CA, USA.  She earned a bachelor's degree in Biochemical Sciences from Harvard University in 1972 (summa cum laude) and her Ph.D. in 1977 from Massachusetts Institute of Technology. She was a Jane Coffin Childs Postdoctoral Fellow at the Memorial Sloan-Kettering Cancer Center from 1977-79.  In 1979, she became Assistant Research Professor at The Salk Institute for Biological Studies, Department of Cancer Biology. In 1982, she was appointed Assistant Professor in the California Institute of Technology, Division of Biology (now Biology & Biological Engineering), and rose through the ranks to become Albert Billings Ruddock Professor of Biology in 2007. She has won multiple teaching awards at Caltech for courses in immunology and molecular biology including the Richard P. Feynman Prize for Excellence in Teaching (2016), and has taught internationally in advanced courses on immunology, developmental biology, and gene regulatory networks.  She has been a member of the Scientific Advisory Boards for five US and international institutes and the Editorial Boards of several prominent journals in immunology and hematology, and has served on three committees for the American Association of Immunologists. She has also served on grant review panels for NIH and NASA and three private foundations, in addition to ad hoc reviewing for other agencies, and has founded or co-organized multiple international conferences in immunology and systems biology. She was elected a Fellow of the American Association for the Advancement of Sciences in 2017.  Her group’s research is at the interface of immunology, stem cell developmental biology, systems biology, and genomics.  She studies gene regulation and development of T lymphocytes, gene networks controlling hematopoietic cell fates, and mechanisms underlying the dynamics of single-cell developmental decisions. 

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