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      Crystal structure of the trithorax group protein Ash2L reveals a Forkhead-like DNA binding domain

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          Abstract

          Human ASH2L is a trithorax group (TrxG) protein and a regulatory subunit of the SET1 family of lysine methyltransferases. Here we report that Ash2L binds DNA employing a Forkhead-like helix-wing-helix (HWH) domain. In vivo, Ash2L HWH domain is required for binding to the β-globin locus control region (LCR), histone H3 Lys4 tri-methylation and maximal expression of the β-globin gene, validating the functional importance of Ash2L DNA binding activity.

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          Regulation of MLL1 H3K4 methyltransferase activity by its core components.

          Yali Dou, Thomas A. Milne, Alexander Ruthenburg … (2006)
          Histone H3 Lys4 (H3K4) methylation is a prevalent mark associated with transcription activation. A common feature of several H3K4 methyltransferase complexes is the presence of three structural components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Here we report the first biochemical reconstitution of a functional four-component mixed-lineage leukemia protein-1 (MLL1) core complex. This reconstitution, combined with in vivo assays, allows direct analysis of the contribution of each component to MLL1 enzymatic activity and their roles in transcriptional regulation. Moreover, taking clues from a crystal structure analysis, we demonstrate that WDR5 mediates interactions of the MLL1 catalytic unit both with the common structural platform and with the histone substrate. Mechanistic insights gained from this study can be generalized to the whole family of SET1-like histone methyltransferases in mammals.
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            p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation.

            Shravanti Rampalli, F. Dilworth, Marjorie Brand … (2007)
            Cell-specific patterns of gene expression are established through the antagonistic functions of trithorax group (TrxG) and Polycomb group (PcG) proteins. Several muscle-specific genes have previously been shown to be epigenetically marked for repression by PcG proteins in muscle progenitor cells. Here we demonstrate that these developmentally regulated genes become epigenetically marked for gene expression (trimethylated on histone H3 Lys4, H3K4me3) during muscle differentiation through specific recruitment of Ash2L-containing methyltransferase complexes. Targeting of Ash2L to specific genes is mediated by the transcriptional regulator Mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 MAPK signaling pathway via phosphorylation of Mef2d. Thus, we provide evidence that signaling pathways regulate the targeting of TrxG-mediated epigenetic modifications at specific promoters during cellular differentiation.
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              Structure/function relationships underlying regulation of FOXO transcription factors.

              V Obsilova, T Obsil (2008)
              The FOXO subgroup of forkhead transcription factors plays a central role in cell-cycle control, differentiation, metabolism control, stress response and apoptosis. Therefore, the function of these important molecules is tightly controlled by a wide range of protein-protein interactions and posttranslational modifications including phosphorylation, acetylation and ubiquitination. The mechanisms by which these processes regulate FOXO activity are mostly elusive. This review focuses on recent advances in structural studies of forkhead transcription factors and the insights they provide into the mechanism of DNA recognition. On the basis of these data, we discuss structural aspects of protein-protein interactions and posttranslational modifications that target the forkhead domain and the nuclear localization signal of FOXO proteins.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Journal ID (iso-abbrev): Nat. Struct. Mol. Biol.
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 26 February 2014
                Publication date (Electronic): 05 June 2011
                Publication date PMC-release: 10 April 2014
                Volume: 18
                Issue: 7
                Pages: 857-859
                Affiliations
                [1 ]Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
                [2 ]The Sprott Center for Stem cell Research, Regenerative medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6 Canada
                [3 ]Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada
                [4 ]Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois 60611, USA
                Author notes
                Corresponding author: Jean-Francois Couture, Contact information: Address: University of Ottawa, Ottawa Institute of Systems Biology, 451 Smyth Road, Roger Guindon Hall, Ottawa, On K1H 8M5, jean-francois.couture@ 123456uottawa.ca , Phone: 613-562-5800-8854, FAX: 613-562-5655
                [5]

                These authors equally contributed to this work.

                Article
                Manuscript ID: CAMS4090
                DOI: 10.1038/nsmb.2093
                PMC ID: 3983046
                PubMed ID: 21642971
                SO-VID: 1842df41-149f-4de6-b67d-72687dc5e972
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                ScienceOpen disciplines: Molecular biology
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                ScienceOpen disciplines: Molecular biology

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