Epigenetic switches during stem cell differentiation

Kloet, Susan.jpg

Polycomb group (PcG) proteins are an evolutionary conserved family of protein complexes that are important for cellular differentiation and development. For example, they play a key role in regulating the expression of Hox gene clusters, which control body-segmentation patterns. PcG assemble into three major protein complexes: PRC1, PRC2 and PR-DUB. PRC2 catalyzes trimethylation of histone H3 at lysine 27, which is an epigenetic modification that plays an important role in gene silencing during development. Although the core subunits of PcG complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation.  

Susan Kloet (photo up), together with colleagues working in the research group headed by Michiel Vermeulen, Dept. of Molecular Biology, theme Cancer development and immune defense  published a paper in Nature Structural and Molecular Biology in which they describe the dynamic interactome and genomic targets of PcG complexes during mouse embryonic stem cell differentiation. The authors found the stoichiometry and genome-wide targets of PRC1 and PRC2 to be highly dynamic during neural differentiation. Intriguingly, they observed a downregulation and loss of PRC2 from chromatin marked with trimethylated histone H3 K27 (H3K27me3) during differentiation, whereas PRC1 was retained at these sites. Additionally, PRC1 was found at enhancer and promoter regions independently of PRC2 binding and H3K27me3. Finally, overexpression of neuronal-specific PRC1 interactors in embryonic stem cells led to increased PRC1 binding to, and decreased expression of, neuronal specific PRC1 target genes. In summary, these integrative analyses uncovered dynamic PcG subcomplexes and their widespread colocalization with active chromatin marks during differentiation.

Publication: The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation. Susan L. Kloet, Matthew M. Makowski, H. Irem Baymaz, Lisa van Voorthuijsen, Ino D. Karemaker, Alexandra Santanach, Pascal W.T.C. Jansen, Luciano Di Croce and Michiel Vermeulen. Nature Structural and Molecular Biology.

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