Chromatin Remodeling and Epigenetic Control of Cell Differentiation
Conference Recording May 01, 2013
About the Speaker
Current position: Professor of Medical Genetics and Epigenetics, Karolinska Institutet 2009-. Chairman for the Swedish Epigenetics network (-2010) and member of the EU Epigenome NoE (-2009). Currently member of two Nordic research networks (2011-) and has recently contributed to a number of community-directed science initiatives in Sweden.
Both the reprogramming and the epigenome maintenance function require SNF2 enzymes, which catalyse nucleosome dynamics. However SNF2 remodeling processes are complex and not easily dissected in humans since there are as many as 53 different SNF2 remodeling factors. Our laboratory is using a well-defined eukaryotic model system namely fission yeast (S. pombe) with a relatively low number of SNF2 enzymes. By MNase mapping of chromatin we find a remarkably uniform pattern of nucleosome positioning in gene coding regions and a clearly defined nucleosome free region (NFR) at active gene promoters in S. pombe. Interestingly, the presence of the histone variant H2A.Z correlates with the absence of NFR at inactive promoters, suggesting that the transition from closed to open promoter structure could be linked to removal of H2A.Z. The SNF2 enzyme Swr1 is required for deposition of H2A.Z whereas another remodeler Chd1 is anti-correlated to H2A.Z. We show that the nucleosome disassembly function of Topoisomerase I is linked to function of the Chd1 remodeler. We propose a model involving a cooperation of Toposiomerase I and SNF2 enzymes in nucleosome disassembly at NFRs and the control of gene expression. We speculate that this mechanism maybe relevant for epigenetic programming of stem cells since Chd1 is required for pluripotency of mouse embryonic stem cells. To study human cell differentiation, we have isolated granulopoietic cell populations at different maturation levels. Preliminary, genome-wide DNA methylation analysis suggests reduction of CpG methylation at some specific genes during the differentiation process and drastic changes in global histone modification levels. We also observe changes of DNA methylation and histone modification patterns in samples from acute myeloid leukemia patients and we are interested in exploring these changes as a prognostic tool in the clinic.
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