Agenda
20/05/2015 - 12:00 - Auditori PRBB

How transcription factors induce cell fate changes


Scientific sessions, CRG Group Leader Seminars

Thomas Graf

Hematopoietic Stem Cells, Transdifferentiation and Reprogramming Group, Gene Regulation, Stem Cells and Cancer Programme, CRG



Thomas Graf was born in Vienna and grew up in Caracas. He did his PhD at the Max Planck Institut fuer Virusforschung in Tuebingen, Germany and a postdoc at Duke University, Durham NC. In 1972 he became a Group Leader at the Max Planck Institut in Tuebingen and later at the German Cancer Research Center in Heidelberg. From 1983 to 1998 he was a Program Coordinator at the EMBL in Heidelberg. After being at the Albert Einstein College of Medicine in New York for 8 years he moved to Europe in 2006 where he is now at the Center for Genomic Regulation in Barcelona, first as a Coordinator and currently as a Senior Scientist.  Thomas Graf has organized conferences on oncogenes, growth control, leukemia, hematopoiesis and stem cells, is an editor/editorial board member of several stem cell journals, served as a Director of the International Society for Stem Cell Research (ISSCR), and is a member of EMBO and Academia Europaea. He has also received a number of awards, including the Paul Ehrlich-Darmstaedter and the Josef Steiner Prize.

In his early work Thomas Graf co-discovered three retrovirally transmitted oncogenes (Myc, ErbB and Myb) and showed that a combination of at least two are required to cause acute leukemia. In the last two decades he has worked on the mechanisms by which cell fates are established during blood cell differentiation. He was among the first to show that fully specialized cells can be reprogrammed into alternative lineages using cell type restricted transcription factors. Recently, he discovered that it is possible to rapidly reprogram blood cells into induced pluripotent cells and at high efficiencies. His group now studies the earliest events during induced cell fate conversions.    

Abstract

To understand how the hundreds of cell types in our body diversify from a single fertilized cell is one of the major challenges in modern biology. A full understanding of the process will not only unveil the mystery of how multicellular organisms develop but will have important repercussions for genetic diseases and regenerative medicine alike. Loss and gain of function experiments have long implicated transcription factors but the most compelling evidence for their role in cell fate decisions comes from overexpression experiments demonstrating that they have the power to force already specialized cells to acquire completely new identities. Two broad processes can be distinguished. Some tissue specific transcription factors, when ectopically expressed, can induce the cells’ transdifferentiation into another specialized cell type. Alternatively, a cocktail of transcription factors can reprogram somatic cells into induced pluripotent stem cells, as described by Yamanaka. In our own work we have discovered that the transcription factor C/EBPa can convert B-lymphocytes into macrophages within a few days and how this happens is a major focus in the lab. Surprisingly, we found that the same transcription factor can also act as a ‘gate opener’, facilitating the accessibility of the Yamanaka factors to closed chromatin and speeding up the reprogramming into iPS cells more than a hundred fold. Using this experimental system, in my talk I will describe recent experiments that have clarified the earliest stages of the reprogramming process.