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      A novel role for the Aurora B kinase in epigenetic marking of silent chromatin in differentiated postmitotic cells

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          Abstract

          Combinatorial modifications of the core histones have the potential to fine-tune the epigenetic regulation of chromatin states. The Aurora B kinase is responsible for generating the double histone H3 modification tri-methylated K9/phosphorylated S10 (H3K9me3/S10ph), which has been implicated in chromosome condensation during mitosis. In this study, we have identified a novel role for Aurora B in epigenetic marking of silent chromatin during cell differentiation. We find that phosphorylation of H3 S10 by Aurora B generates high levels of the double H3K9me3/S10ph modification in differentiated postmitotic cells and also results in delocalisation of HP1β away from heterochromatin in terminally differentiated plasma cells. Microarray analysis of the H3K9me3/S10ph modification shows a striking increase in the modification across repressed genes during differentiation of mesenchymal stem cells. Our results provide evidence that the Aurora B kinase has a role in marking silent chromatin independently of the cell cycle and suggest that targeting of Aurora B-mediated phosphorylation of H3 S10 to repressed genes could be a mechanism for epigenetic silencing of gene expression.

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          Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.

          A Bannister, P Zegerman, J F Partridge … (2001)
          Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing. The chromo domain of HP1 is necessary for both targeting and transcriptional repression. In the fission yeast Schizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equivalent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylase. Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is identified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila, abolishes methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe shows that the methylase activity of Clr4 is necessary for the correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a 'methyl marker' on histone H3, which is then recognized by HP1 through its chromo domain. This model may also explain the stable inheritance of the heterochromatic state.
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            The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint

            Silke Hauf, Richard Cole, Sabrina LaTerra … (2003)
            The proper segregation of sister chromatids in mitosis depends on bipolar attachment of all chromosomes to the mitotic spindle. We have identified the small molecule Hesperadin as an inhibitor of chromosome alignment and segregation. Our data imply that Hesperadin causes this phenotype by inhibiting the function of the mitotic kinase Aurora B. Mammalian cells treated with Hesperadin enter anaphase in the presence of numerous monooriented chromosomes, many of which may have both sister kinetochores attached to one spindle pole (syntelic attachment). Hesperadin also causes cells arrested by taxol or monastrol to enter anaphase within <1 h, whereas cells in nocodazole stay arrested for 3–5 h. Together, our data suggest that Aurora B is required to generate unattached kinetochores on monooriented chromosomes, which in turn could promote bipolar attachment as well as maintain checkpoint signaling.
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              Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential.

              Alexandra Peister, Jason A. Mellad, Benjamin L Larson … (2004)
              For reasons that are not apparent, it has been difficult to isolate and expand the adult stem cells referred to as mesenchymal stem cells or marrow stromal cells (MSCs) from murine bone marrow. We developed a protocol that provides rapidly expanding MSCs from 5 strains of inbred mice. The MSCs obtained from 5 different strains of mice were similar to human and rat MSCs in that they expanded more rapidly if plated at very low density, formed single-cell-derived colonies, and readily differentiated into either adipocytes, chondrocytes, or mineralizing cells. However, the cells from the 5 strains differed in their media requirements for optimal growth, rates of propagation, and presence of the surface epitopes CD34, stem cell antigen-1 (Sca-1), and vascular cell adhesion molecule 1 (VCAM-1). The protocol should make it possible to undertake a large number of experiments with MSCs in transgenic mice that have previously not been possible. The differences among MSCs from different strains may explain some of the conflicting data recently published on the engraftment of mouse MSCs or other bone marrow cells into nonhematopoietic tissues.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO J
                Title: The EMBO Journal
                Publisher: Nature Publishing Group
                ISSN (Print): 0261-4189
                ISSN (Electronic): 1460-2075
                Publication date (Print): 14 November 2007
                Publication date (Electronic): 18 October 2007
                Volume: 26
                Issue: 22
                Pages: 4657-4669
                Affiliations
                [1 ]Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK
                [2 ]Haemostasis and Thrombosis Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK
                Author notes
                [a ]Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Tel.: +44 20 8383 8237 (PS); Tel.: +44 20 8383 8233 (ND); Fax: +44 20 8383 8338; E-mail: pierangela.sabbattini@ 123456csc.mrc.ac.uk or niall.dillon@ 123456csc.mrc.ac.uk
                Article
                Publisher Item ID: 7601875
                DOI: 10.1038/sj.emboj.7601875
                PMC ID: 2048755
                PubMed ID: 17948062
                SO-VID: 7175523d-74d0-4083-b969-fa2d2938f314
                Copyright © Copyright © 2007, European Molecular Biology Organization
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited.This license does not permit commercial exploitation or the creation of derivative works without specific permission.

                History
                Date received : 2 April 2007
                Date accepted : 14 September 2007
                Page count
                Pages: 13
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: epigenetic regulation,chromatin,aurora b
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: epigenetic regulation, chromatin, aurora b

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