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Nucleic Acids Res. 2016 Jun 2;44(10):4703-20. doi: 10.1093/nar/gkw105. Epub 2016 Feb 23.

A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes.

Author information

1
University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany franz.oswald@uni-ulm.de.
2
Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
3
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany Spemann Graduate School of Biology and Medicine (SGBM), Faculty of Biology, Albert Ludwigs University Freiburg, Germany.
4
Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas-Universidad Miguel Hernández, Campus de Sant Joan, Alicante, Spain.
5
Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
6
University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
7
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267, USA.
8
Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany International Graduate School in Molecular Medicine Ulm (IGradU), Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
9
Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
10
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
11
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany Tilman.Borggrefe@biochemie.med.uni-giessen.de.

Abstract

The transcriptional shift from repression to activation of target genes is crucial for the fidelity of Notch responses through incompletely understood mechanisms that likely involve chromatin-based control. To activate silenced genes, repressive chromatin marks are removed and active marks must be acquired. Histone H3 lysine-4 (H3K4) demethylases are key chromatin modifiers that establish the repressive chromatin state at Notch target genes. However, the counteracting histone methyltransferase required for the active chromatin state remained elusive. Here, we show that the RBP-J interacting factor SHARP is not only able to interact with the NCoR corepressor complex, but also with the H3K4 methyltransferase KMT2D coactivator complex. KMT2D and NCoR compete for the C-terminal SPOC-domain of SHARP. We reveal that the SPOC-domain exclusively binds to phosphorylated NCoR. The balance between NCoR and KMT2D binding is shifted upon mutating the phosphorylation sites of NCoR or upon inhibition of the NCoR kinase CK2β. Furthermore, we show that the homologs of SHARP and KMT2D in Drosophila also physically interact and control Notch-mediated functions in vivo Together, our findings reveal how signaling can fine-tune a committed chromatin state by phosphorylation of a pivotal chromatin-modifier.

PMID:
26912830
PMCID:
PMC4889922
DOI:
10.1093/nar/gkw105
[Indexed for MEDLINE]
Free PMC Article

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