Nathan, D. et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev. 20, 966-976

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Genes & Development (Impact Factor: 10.8). 05/2006; 20(8):966-76. DOI: 10.1101/gad.1404206
Source: PubMed


Covalent histone post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation play pivotal roles in regulating many cellular processes, including transcription, response to DNA damage, and epigenetic control. Although positive-acting post-translational modifications have been studied in Saccharomyces cerevisiae, histone modifications that are associated with transcriptional repression have not been shown to occur in this yeast. Here, we provide evidence that histone sumoylation negatively regulates transcription in S. cerevisiae. We show that all four core histones are sumoylated and identify specific sites of sumoylation in histones H2A, H2B, and H4. We demonstrate that histone sumoylation sites are involved directly in transcriptional repression. Further, while histone sumoylation occurs at all loci tested throughout the genome, slightly higher levels occur proximal to telomeres. We observe a dynamic interplay between histone sumoylation and either acetylation or ubiquitylation, where sumoylation serves as a potential block to these activating modifications. These results indicate that sumoylation is the first negative histone modification to be identified in S. cerevisiae and further suggest that sumoylation may serve as a general dynamic mark to oppose transcription.

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Available from: Milos Dokmanovic
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    • "It is intriguing, nevertheless, how SUMO correlates with this effect. All core histones (H2A, H2B, H3 and H4) were found to be modified by SUMO in K residues that do not match the consensus, similar to what has been reported for H2A and H2B SUMOylation sites in yeast and humans (Nathan et al., 2006; Hendriks et al., 2014; Tammsalu et al., 2014). Since histones are very abundant proteins, they are expected to be easily detected when general SUMOylation patterns are analysed by Western blot; however, it is difficult to predict the apparent molecular weight of SUMOylated histones mainly because they can be SUMOylated at multiple K residues. "
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    ABSTRACT: SUMOylation is an important post-translational modification conserved in eukaryotic organisms. In Trypanosoma brucei, SUMO is essential in procyclic and bloodstream forms. Furthermore, SUMO has been linked to the antigenic variation process, as a highly SUMOylated focus was recently identified within chromatin-associated proteins of the active VSG expression site. We aimed to establish a reliable strategy to identify SUMO conjugates in T. brucei. We expressed various tagged variants of SUMO from the endogenous locus. His-HA-TbSUMO was useful to validate the tag functionality but SUMO conjugates were not enriched enough over contaminants after affinity purification. A Lys-deficient SUMO version, created to reduce contaminants by Lys-C digestion, was able to overcome this issue but did not allow mapping many SUMOylation sites. This cell line was in turn useful to demonstrate that polySUMO chains are not essential for parasite viability. Finally, a His-HA-TbSUMO(T106K) version allowed the purification of SUMO conjugates and, after digestion with Lys-C, the enrichment for diGly-Lys peptides using specific antibodies. This site specific proteomic strategy led us to identify 45 SUMOylated proteins and 53 acceptor sites unambiguously. SUMOylated proteins belong mainly to nuclear processes such as DNA replication and repair, transcription, rRNA biogenesis, and chromatin remodelling, among others. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2015 · Cellular Microbiology
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    • "For instance, sumoylation of the repressor complex Tup1- Ssn6 inhibits transcription (Texari et al. 2013). Furthermore, sumoylation of histones inhibits transcription, although the physiological relevance remains unknown (Nathan et al. 2006). Recent studies indicate that Sumo can also have a positive role (Rosonina et al. 2010). "
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    ABSTRACT: Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Whole-genome expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs. Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Mar 2015 · Genome Research
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    • "A second mechanism could rely on HDAC activation by SUMO because it was observed that lowered HDAC sumoylation may indirectly lead to higher histone acetylation (David et al. 2002; Cheng et al. 2004). In Saccharomyces cerevisiae, a higher level of H2B- SUMO was observed at telomeres than at more internal chromosomal sites, which may suggest the participation of histone sumoylation in telomeric silencing (Nathan et al. 2006). It is unclear whether sumoylation directly alters nucleosomal structure or packing and whether it promotes or inhibits interactions with non-histone proteins. "
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    ABSTRACT: The complexity of the genome is regulated by epigenetic mechanisms, which act on the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in various biological processes, including embryonic development, cell differentiation, neurogenesis, and adult cell renewal. In the last few years, it has become clear that the number of players identified in the regulation of chromatin structure and function is still increasing. In addition to well-known phenomena, including DNA methylation and histone modification, new, important elements, including nucleosome mobility, histone tail clipping, and regulatory ncRNA molecules, are being discovered. The present paper provides the current state of knowledge about the role of 16 different histone post-translational modifications, nucleosome positioning, and histone tail clipping in the structure and function of chromatin. We also emphasize the significance of cross-talk among chromatin marks and ncRNAs in epigenetic control.
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