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Nucleic Acids Res. 2018 Sep 19;46(16):8197-8215. doi: 10.1093/nar/gky551.

Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response.

Author information

1
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
2
Spemann Graduate School of Biology and Medicine (SGBM), Albertstrasse 19A, 79104 Freiburg, Germany.
3
Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Campus de Sant Joan, Apartado 18, 03550 Sant Joan, Alicante, Spain.
4
Genomics Core Facility, Institute of Molecular Oncology, Philipps-University, Hans-Meerwein-Str. 3, 35043 Marburg, Germany.
5
Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
6
Department of Internal Medicine II, Universities Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany.
7
Bioinformatics and Systems Biology, University of Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
8
Institute for Genetics, University of Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
9
University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany.

Abstract

A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation.

PMID:
29986055
PMCID:
PMC6144792
DOI:
10.1093/nar/gky551
[Indexed for MEDLINE]
Free PMC Article

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