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      N-alpha-terminal Acetylation of Histone H4 Regulates Arginine Methylation and Ribosomal DNA Silencing

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          Abstract

          Post-translational modifications of histones play a key role in DNA-based processes, like transcription, by modulating chromatin structure. N-terminal acetylation is unique among the numerous histone modifications because it is deposited on the N-alpha amino group of the first residue instead of the side-chain of amino acids. The function of this modification and its interplay with other internal histone marks has not been previously addressed. Here, we identified N-terminal acetylation of H4 (N-acH4) as a novel regulator of arginine methylation and chromatin silencing in Saccharomyces cerevisiae. Lack of the H4 N-alpha acetyltransferase (Nat4) activity results specifically in increased deposition of asymmetric dimethylation of histone H4 arginine 3 (H4R3me2a) and in enhanced ribosomal-DNA silencing. Consistent with this, H4 N-terminal acetylation impairs the activity of the Hmt1 methyltransferase towards H4R3 in vitro. Furthermore, combinatorial loss of N-acH4 with internal histone acetylation at lysines 5, 8 and 12 has a synergistic induction of H4R3me2a deposition and rDNA silencing that leads to a severe growth defect. This defect is completely rescued by mutating arginine 3 to lysine (H4R3K), suggesting that abnormal deposition of a single histone modification, H4R3me2a, can impact on cell growth. Notably, the cross-talk between N-acH4 and H4R3me2a, which regulates rDNA silencing, is induced under calorie restriction conditions. Collectively, these findings unveil a molecular and biological function for H4 N-terminal acetylation, identify its interplay with internal histone modifications, and provide general mechanistic implications for N-alpha-terminal acetylation, one of the most common protein modifications in eukaryotes.

          Author Summary

          The genome of eukaryotic cells is packaged into nucleosomes consisting of an octamer of histone proteins that is wrapped around by DNA. Histone proteins are often modified with chemical groups that can influence the arrangement of nucleosomes and thereby affect DNA-based processes like transcription. Histone N-terminal acetylation, which comprises the addition of a chemical group at the tip of the histone tail, is an abundant modification whose function is unknown. In this work, we show that N-terminal acetylation of histone H4 can strongly inhibit the occurrence of a neighboring modification, namely dimethylation at the third arginine. To do this, N-terminal acetylation cooperates with other internal lysine acetylation marks. We find that the communication amongst these histone modifications is necessary for controlling the expression of ribosomal RNA genes that are required for protein synthesis and cell growth. Our experiments show that in the absence of both N-terminal acetylation and lysine acetylation there is a strong increase in H4 arginine 3 dimethylation levels leading to cell lethality. This growth defect can be rescued by a point mutation on H4 that blocks methylation at position 3. Together, our results unveil a molecular and biological function for the previously uncharacterized N-terminal acetylation of histones.

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          Most cited references48

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          A rapid and simple method for preparation of RNA from Saccharomyces cerevisiae.

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            Histone H4 lysine-16 acetylation regulates cellular lifespan

            Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD+-dependent deacetylases or ADP-ribosylases, promote longevity in diverse organisms; however, their molecular mechanisms in aging regulation remain poorly understood. Yeast Sir2, the founding member of the family, establishes and maintains chromatin silencing by removing H4 lysine 16 acetylation and bringing in other silencing proteins. Here we show an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing aging models for yeast, may represent an evolutionarily conserved function of Sirtuins in regulation of replicative aging by maintenance of intact telomeric chromatin.
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              Ribosome synthesis in Saccharomyces cerevisiae.

              The synthesis of ribosomes is one of the major metabolic pathways in all cells. In addition to around 75 individual ribosomal proteins and 4 ribosomal RNAs, synthesis of a functional eukaryotic ribosome requires a remarkable number of trans-acting factors. Here, we will discuss the recent, and often surprising, advances in our understanding of ribosome synthesis in the yeast Saccharomyces cerevisiae. These will underscore the unexpected complexity of eukaryotic ribosome synthesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                September 2013
                September 2013
                19 September 2013
                : 9
                : 9
                : e1003805
                Affiliations
                [1]Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
                Medical Research Council Human Genetics Unit, United Kingdom
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: VS DMS AK. Performed the experiments: VS DMS DK AH AK. Analyzed the data: VS DMS AK. Wrote the paper: AK.

                Article
                PGENETICS-D-13-01010
                10.1371/journal.pgen.1003805
                3778019
                24068969
                889c3c6a-879e-4b9d-84bb-c86c081c2f88
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 April 2013
                : 3 August 2013
                Page count
                Pages: 12
                Funding
                This work was supported by grants from the European Research Council (ERC-2010-Stg, N.260797, ChromatinModWeb) and the Cyprus Research Promotion Foundation (Health/Bio/0609(BE)/09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Genetics
                Genetics

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