Mechanisms of transcription factor induced transdifferentiation and reprogramming to pluripotency
Thomas Graf, Gene Regulation, Stem Cells and Differentiation Programme, CRG / Pompeu Fabra University
Work by many laboratories has shown that even fully differentiated cells are remarkably plastic and can be reprogrammed into alternative fates. This discovery has revolutionized our understanding of how cell decide what to become and has major implications for the modeling and therapy of diseases that affect the production of differentiated cells.
Our earlier work has shown that the myeloid transcription factor C/EBPa induces B cells to transdifferentiate into macrophages at high efficiencies. We have now found that the process forces the intersection of two enhancer pathways that become activated during normal hematopoietic differentiation.
Recently we reported that the transient expression of C/EBPa in B cells, followed by expression of the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (OSKM), poises the cells for very rapid and highly efficient reprogramming into induced pluripotent stem cells. Our findings have removed a major obstacle in studying cell reprogramming and permitted us to investigate how C/EBPa leads to the almost immediate accessibility of pluripotency genes to binding by Oct4. Our new data provide unprecedented insights into the earliest events leading to activation of the pluripotency gene regulatory network, resulting in somatic cell reprogramming.