Article | Published:

Regulation of transcription by the MLL2 complex and MLL complex–associated AKAP95

Nature Structural & Molecular Biology volume 20, pages 11561163 (2013) | Download Citation

Abstract

Although histone H3 Lys4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription, through specific MLL family members, is scarce. Here we have purified a human MLL2 (Kmt2b) complex that is highly active in H3K4 methylation and chromatin transcription in a cell-free system. This effect requires S-adenosyl methionine and intact H3K4, thus establishing a direct and causal role for MLL2-mediated H3K4 methylation in transcription. We also show that human AKAP95, a chromatin-associated protein, physically and functionally associates with MLL complexes and directly enhances their methyltransferase activity. Ectopic AKAP95 stimulates expression of a chromosomal reporter gene in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid–mediated gene induction in embryonic stem cells. These results demonstrate an important role for AKAP95 in regulating histone methylation and gene expression, particularly during cell-fate transitions.

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Acknowledgements

We thank Kazusa DNA Research Institute (Japan) for providing the cDNA KIAA0304. We thank J. Kim (Rockefeller University (RU)) for histone H3 and H4 with mutations in acetylation sites, E. McIntush (Bethyl Laboratories) and C. Hughes (RU) for the antibody to DPY30, Q. Yang (RU) for multiple valuable reagents, J. Wysocka (Stanford University) for the antibody to WDR5, A. Goldberg and D. Allis (RU) for LIF and Z. Fu and Z. Yan (RU) for excellent technical assistance. H.J. was supported by a fellowship from the Leukemia and Lymphoma Society, and X.L. was supported as a recipient of the C.H. Li Memorial Scholar Award. This work was supported by grants from the US National Institutes of Health (CA129325 and DK071900) and the Ellison Medical Foundation (AG-SS-2665-11) to R.G.R. and by a Leukemia and Lymphoma Society SCOR grant (7132-08).

Author information

Author notes

    • Hao Jiang
    •  & Xiangdong Lu

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, New York, USA.

    • Hao Jiang
    • , Xiangdong Lu
    • , Miho Shimada
    • , Yali Dou
    • , Zhanyun Tang
    •  & Robert G Roeder
  2. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Hao Jiang
  3. UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Hao Jiang

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Contributions

H.J. and X.L. conceived of the project, designed and performed the experiments, analyzed the data and wrote the paper. M.S. and Y.D. performed experiments. Z.T. generated the K4Q mutant octamer. R.G.R. conceived of the project, analyzed the data, wrote the paper, supervised the project and had overall responsibility for the joint research.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert G Roeder.

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https://doi.org/10.1038/nsmb.2656

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