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      The histone variant H2A.Z in gene regulation

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          Abstract

          The histone variant H2A.Z is involved in several processes such as transcriptional control, DNA repair, regulation of centromeric heterochromatin and, not surprisingly, is implicated in diseases such as cancer. Here, we review the recent developments on H2A.Z focusing on its role in transcriptional activation and repression. H2A.Z, as a replication-independent histone, has been studied in several model organisms and inducible mammalian model systems. Its loading machinery and several modifying enzymes have been recently identified, and some of the long-standing discrepancies in transcriptional activation and/or repression are about to be resolved. The buffering functions of H2A.Z, as supported by genome-wide localization and analyzed in several dynamic systems, are an excellent example of transcriptional control. Posttranslational modifications such as acetylation and ubiquitination of H2A.Z, as well as its specific binding partners, are in our view central players in the control of gene expression. Understanding the key-mechanisms in either turnover or stabilization of H2A.Z-containing nucleosomes as well as defining the H2A.Z interactome will pave the way for therapeutic applications in the future.

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.

            Acetylation of proteins on lysine residues is a dynamic posttranslational modification that is known to play a key role in regulating transcription and other DNA-dependent nuclear processes. However, the extent of this modification in diverse cellular proteins remains largely unknown, presenting a major bottleneck for lysine-acetylation biology. Here we report the first proteomic survey of this modification, identifying 388 acetylation sites in 195 proteins among proteins derived from HeLa cells and mouse liver mitochondria. In addition to regulators of chromatin-based cellular processes, nonnuclear localized proteins with diverse functions were identified. Most strikingly, acetyllysine was found in more than 20% of mitochondrial proteins, including many longevity regulators and metabolism enzymes. Our study reveals previously unappreciated roles for lysine acetylation in the regulation of diverse cellular pathways outside of the nucleus. The combined data sets offer a rich source for further characterization of the contribution of this modification to cellular physiology and human diseases.
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              An improved zinc-finger nuclease architecture for highly specific genome editing.

              Genome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalytically active nuclease complex. Using the current ZFN architecture, however, cleavage-competent homodimers may also form that can limit safety or efficacy via off-target cleavage. Here we develop an improved ZFN architecture that eliminates this problem. Using structure-based design, we engineer two variant ZFNs that efficiently cleave DNA only when paired as a heterodimer. These ZFNs modify a native endogenous locus as efficiently as the parental architecture, but with a >40-fold reduction in homodimer function and much lower levels of genome-wide cleavage. This architecture provides a general means for improving the specificity of ZFNs as gene modification reagents.
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                Author and article information

                Contributors
                Benedetto.Giaimo@biochemie.med.uni-giessen.de
                Francesca.Ferrante@biochemie.med.uni-giessen.de
                Andreas.Herchenroether@gen.bio.uni-giessen.de
                Sandra.Hake@gen.bio.uni-giessen.de
                Tilman.Borggrefe@biochemie.med.uni-giessen.de
                Journal
                Epigenetics Chromatin
                Epigenetics Chromatin
                Epigenetics & Chromatin
                BioMed Central (London )
                1756-8935
                14 June 2019
                14 June 2019
                2019
                : 12
                : 37
                Affiliations
                [1 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Institute of Biochemistry, , University of Giessen, ; Friedrichstrasse 24, 35392 Giessen, Germany
                [2 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Institute for Genetics, , University of Giessen, ; Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany
                Author information
                http://orcid.org/0000-0003-4325-5452
                Article
                274
                10.1186/s13072-019-0274-9
                6570943
                31200754
                198349e3-996e-436a-9e16-0975079a30d6
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 March 2019
                : 23 April 2019
                Funding
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: TRR81
                Award ID: BO1639/5-1
                Award Recipient :
                Funded by: UKGM grant
                Award ID: BDG-04
                Award Recipient :
                Funded by: ECCPS
                Award ID: SH1
                Award ID: TB1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009103, Von-Behring-Röntgen-Stiftung;
                Award ID: BO04
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Genetics
                h2a.z,h2av,histone variant,p400,domino,tip60,crispr/cas9
                Genetics
                h2a.z, h2av, histone variant, p400, domino, tip60, crispr/cas9

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