IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36368-5.html
   My bibliography  Save this article

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

Author

Listed:
  • Dustin C. Becht

    (University of Colorado School of Medicine)

  • Brianna J. Klein

    (University of Colorado School of Medicine)

  • Akinori Kanai

    (the University of Tokyo)

  • Suk Min Jang

    (Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division)

  • Khan L. Cox

    (Ohio State University)

  • Bing-Rui Zhou

    (National Institutes of Health)

  • Sabrina K. Phanor

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Yi Zhang

    (University of Colorado School of Medicine)

  • Ruo-Wen Chen

    (Ohio State University)

  • Christopher C. Ebmeier

    (University of Colorado)

  • Catherine Lachance

    (Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division)

  • Maxime Galloy

    (Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division)

  • Amelie Fradet-Turcotte

    (Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division)

  • Martha L. Bulyk

    (Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Yawen Bai

    (National Institutes of Health)

  • Michael G. Poirier

    (Ohio State University)

  • Jacques Côté

    (Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division)

  • Akihiko Yokoyama

    (National Cancer Center)

  • Tatiana G. Kutateladze

    (University of Colorado School of Medicine)

Abstract

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.

Suggested Citation

  • Dustin C. Becht & Brianna J. Klein & Akinori Kanai & Suk Min Jang & Khan L. Cox & Bing-Rui Zhou & Sabrina K. Phanor & Yi Zhang & Ruo-Wen Chen & Christopher C. Ebmeier & Catherine Lachance & Maxime Gal, 2023. "MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36368-5
    DOI: 10.1038/s41467-023-36368-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36368-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-36368-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
    2. Catherine A. Musselman & Matthew D. Gibson & Erik W. Hartwick & Justin A. North & Jovylyn Gatchalian & Michael G. Poirier & Tatiana G. Kutateladze, 2013. "Binding of PHF1 Tudor to H3K36me3 enhances nucleosome accessibility," Nature Communications, Nature, vol. 4(1), pages 1-9, December.
    3. Yi Zhang & Kyle Brown & Yucong Yu & Ziad Ibrahim & Mohamad Zandian & Hongwen Xuan & Steven Ingersoll & Thomas Lee & Christopher C. Ebmeier & Jiuyang Liu & Daniel Panne & Xiaobing Shi & Xiaojun Ren & T, 2021. "Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Brianna J. Klein & Suk Min Jang & Catherine Lachance & Wenyi Mi & Jie Lyu & Shun Sakuraba & Krzysztof Krajewski & Wesley W. Wang & Simone Sidoli & Jiuyang Liu & Yi Zhang & Xiaolu Wang & Becka M. Warfi, 2019. "Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    5. Michael Grunstein, 1997. "Histone acetylation in chromatin structure and transcription," Nature, Nature, vol. 389(6649), pages 349-352, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Thomas B. Kepler & Timothy C. Elston, 2001. "Stochasticity in Transcriptional Regulation: Origins, Consequences and Mathematical Representations," Working Papers 01-06-033, Santa Fe Institute.
    2. Avinash B. Patel & Jinkang Qing & Kelly H. Tam & Sara Zaman & Maria Luiso & Ishwar Radhakrishnan & Yuan He, 2023. "Cryo-EM structure of the Saccharomyces cerevisiae Rpd3L histone deacetylase complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Jayme L. Dahlin & Bruce K. Hua & Beth E. Zucconi & Shawn D. Nelson & Shantanu Singh & Anne E. Carpenter & Jonathan H. Shrimp & Evelyne Lima-Fernandes & Mathias J. Wawer & Lawrence P. W. Chung & Ayushi, 2023. "Reference compounds for characterizing cellular injury in high-content cellular morphology assays," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Ziad Ibrahim & Tao Wang & Olivier Destaing & Nicola Salvi & Naghmeh Hoghoughi & Clovis Chabert & Alexandra Rusu & Jinjun Gao & Leonardo Feletto & Nicolas Reynoird & Thomas Schalch & Yingming Zhao & Ma, 2022. "Structural insights into p300 regulation and acetylation-dependent genome organisation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    5. Yosuke Komata & Akinori Kanai & Takahiro Maeda & Toshiya Inaba & Akihiko Yokoyama, 2023. "MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Sung-Yeon Hwang & Hyewon Kim & Danielle Denisko & Boxun Zhao & Dohoon Lee & Jiseok Jeong & Jinuk Kim & Kiwon Park & Junhyun Park & Dongjoon Jeong & Sehong Park & Hee-Jung Choi & Sun Kim & Eunjung Alic, 2024. "Human cytomegalovirus harnesses host L1 retrotransposon for efficient replication," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36368-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.