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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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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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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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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DOI: https://doi.org/10.1038/nsmb.2093
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