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Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain

Nature Structural & Molecular Biology volume 18, pages 857–859 (2011)Cite this article

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Abstract

Absent, small or homeotic discs–like 2 (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 using a forkhead-like helix-wing-helix (HWH) domain. In vivo, the ASH2L HWH domain is required for binding to the β-globin locus control region, histone H3 Lys4 (H3K4) trimethylation and maximal expression of the β-globin gene (Hbb-1), validating the functional importance of the ASH2L DNA binding domain.

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Figure 1: ASH2L is composed of a C4 zinc finger and a structurally conserved helix-wing-helix domain.
Figure 2: The N-terminal domain of ASH2L binds DNA.
Figure 3: Role of ASH2L HWH domain in the regulation of β-globin gene expression.

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Acknowledgements

We wish to thank J. Dilworth (Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute) for the Ash2L antibody and other reagents. We are highly indebted to R.C. Trievel, who facilitated part of this work. This work was supported by Canadian Institutes of Health Research (CIHR) grants to J.-F.C. (191666) and M.B. (MOP-89834). J.-F.C. holds a Canada Research Chair in Structural Biology and Epigenetics. P.Z. is sponsored by a Natural Sciences and Engineering Research Council of Canada (NSERC) fellowship. C.-P.C. is supported by a CIHR/Thalassemia Foundation of Canada postdoctoral fellowship.

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Author notes

  1. Sabina Sarvan, Vanja Avdic and Véronique Tremblay: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Ottawa Institute of Systems Biology, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    Sabina Sarvan, Vanja Avdic, Véronique Tremblay, Pamela Zhang, Sylvain Lanouette, Alexandre Blais & Jean-François Couture

  2. The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Chandra-Prakash Chaturvedi, Alexandre Blais & Marjorie Brand

  3. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Chandra-Prakash Chaturvedi & Marjorie Brand

  4. Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    Joseph S Brunzelle

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  1. Sabina Sarvan
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Contributions

J.-F.C. and M.B. designed the experiments. S.S. and V.A were responsible for doing the EMSA and analyzing the crystal structure. V.T. did the SELEX and validated the ASH2L target genes. C.-P.C. carried out the ChIP and qRT-PCR studies. P.Z. and S.L. did the methyltransferase assays and sequence alignment, respectively. J.S.B. collected the data and calculated the initial phases of the model. A.B. analyzed the SELEX data. J.-F.C. provided scientific direction for the project and wrote the manuscript. J.S.B., A.B. and M.B commented on the paper.

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Correspondence to Jean-François Couture.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 3268 kb)

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Sarvan, S., Avdic, V., Tremblay, V. et al. Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nat Struct Mol Biol 18, 857–859 (2011). https://doi.org/10.1038/nsmb.2093

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