PRBB-CRG Sessions Ken Zaret
PRBB-CRG Sessions Ken Zaret
16/11/201812:00MARIE CURIEPRBB-CRG SessionsKen ZaretPerelman School of Medecine, University of Pennslvania, US"Overcoming Chromatin Barriers to Change Cell Fate"Host: Thomas Graf (CRG)Abstract:Kenneth S. Zaret, Ryan McCarthy, Kelsey Kaeding, Greg Donahue, Dario Nicetto
Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, U.S.A
The incredible diversity of animals and plants depends upon embryonic cells to differentiate into various cell types and to stably retain such differentiation after development. In the future, we will be able to control cell fate at will by knowing how cells initiate fate changes and how to overcome chromatin barriers that promote differentiation stability. To this end, we investigate the basis by which changes in cell fate involve dramatic and discrete switches in gene expression programs and how such switches are locked in by chromatin states that impede further changes. We have proposed that pioneer transcription factors provide a basis for initiating cell fate changes by virtue of their ability to scan nucleosomal DNA, recognize a partial motif on the nucleosome surface, and initiate cooperative events that impart a functional identity to otherwise naïve or silent chromatin. Pioneer factors enable chromatin opening or closure, depending upon their combinatorial recruitment of additional factors. FoxA1, a paradigm pioneer factor, helps open locally compacted chromatin by displacing linker histone and by using a C-terminal domain to disrupt interactions between adjacent nucleosomes. Recent studies from our lab show that other pioneer factors in recombinant form, such as PU.1 and C/EBPalpha, are sufficient to open a targeted nucleosome in chromatin arrays that are compacted with linker histone, in vitro. Yet there remain heterochromatic regions of the genome that are difficult for nearly all regulatory factors to access, including many pioneer factors, and that harbor genes required for terminal differentiation. By combining biophysical methods, proteomics, and genomics, we discovered an unexpectedly diverse set of proteins embedded in heterochromatin. By genetically targeting such proteins, we are discerning how to overcome heterochromatin barriers to enhance cellular reprogramming. We find that marked dynamics in heterochromatin occur during organogenesis, which may focus regulatory factor access to the genome during embryonic differentiation and growth. Our new view is that a combination of pioneer transcription factors along with disruption of heterochromatic domains is necessary to most efficiently reprogram one cell type into another.