IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42650-3.html
   My bibliography  Save this article

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

Author

Listed:
  • Dongmei Wang

    (Qilu Hospital of Shandong University
    Qilu Hospital of Shandong University)

  • Tao Sun

    (Qilu Hospital of Shandong University
    Qilu Hospital of Shandong University)

  • Yuan Xia

    (Qilu Hospital of Shandong University)

  • Zhe Zhao

    (Qilu Hospital of Shandong University)

  • Xue Sheng

    (Qilu Hospital of Shandong University)

  • Shuying Li

    (Qilu Hospital of Shandong University)

  • Yuechan Ma

    (Qilu Hospital of Shandong University)

  • Mingying Li

    (Qilu Hospital of Shandong University)

  • Xiuhua Su

    (Qilu Hospital of Shandong University)

  • Fan Zhang

    (Qilu Hospital of Shandong University)

  • Peng Li

    (Qilu Hospital of Shandong University)

  • Daoxin Ma

    (Qilu Hospital of Shandong University
    Qilu Hospital of Shandong University)

  • Jingjing Ye

    (Qilu Hospital of Shandong University)

  • Fei Lu

    (Qilu Hospital of Shandong University)

  • Chunyan Ji

    (Qilu Hospital of Shandong University
    Qilu Hospital of Shandong University)

Abstract

CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

Suggested Citation

  • Dongmei Wang & Tao Sun & Yuan Xia & Zhe Zhao & Xue Sheng & Shuying Li & Yuechan Ma & Mingying Li & Xiuhua Su & Fan Zhang & Peng Li & Daoxin Ma & Jingjing Ye & Fei Lu & Chunyan Ji, 2023. "Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42650-3
    DOI: 10.1038/s41467-023-42650-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42650-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42650-3?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. Lei Zhang & Xinran Geng & Fangfang Wang & Jinshan Tang & Yu Ichida & Arishya Sharma & Sora Jin & Mingyue Chen & Mingliang Tang & Franklin Mayca Pozo & Wenxiu Wang & Janet Wang & Michal Wozniak & Xiaox, 2022. "53BP1 regulates heterochromatin through liquid phase separation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Alexander Arthur Wurm & Polina Zjablovskaja & Miroslava Kardosova & Dennis Gerloff & Daniela Bräuer-Hartmann & Christiane Katzerke & Jens-Uwe Hartmann & Touati Benoukraf & Stephan Fricke & Nadja Hilge, 2017. "Disruption of the C/EBPα—miR-182 balance impairs granulocytic differentiation," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    3. Bi Shi & Wei Li & Yansu Song & Zhenjia Wang & Rui Ju & Aleksandra Ulman & Jing Hu & Francesco Palomba & Yanfang Zhao & John Philip Le & William Jarrard & David Dimoff & Michelle A. Digman & Enrico Gra, 2021. "UTX condensation underlies its tumour-suppressive activity," Nature, Nature, vol. 597(7878), pages 726-731, September.
    4. Lei Zhang & Xinran Geng & Fangfang Wang & Jinshan Tang & Yu Ichida & Arishya Sharma & Sora Jin & Mingyue Chen & Mingliang Tang & Franklin Mayca Pozo & Wenxiu Wang & Janet Wang & Michal Wozniak & Xiaox, 2022. "Author Correction: 53BP1 regulates heterochromatin through liquid phase separation," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    5. Theodore P. Braun & Mariam Okhovat & Cody Coblentz & Sarah A. Carratt & Amy Foley & Zachary Schonrock & Brittany M. Curtiss & Kimberly Nevonen & Brett Davis & Brianna Garcia & Dorian LaTocha & Benjami, 2019. "Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    6. Ryan J. Ries & Sara Zaccara & Pierre Klein & Anthony Olarerin-George & Sim Namkoong & Brian F. Pickering & Deepak P. Patil & Hojoong Kwak & Jun Hee Lee & Samie R. Jaffrey, 2019. "m6A enhances the phase separation potential of mRNA," Nature, Nature, vol. 571(7765), pages 424-428, July.
    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. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Min Lee & Hyungseok C. Moon & Hyeonjeong Jeong & Dong Wook Kim & Hye Yoon Park & Yongdae Shin, 2024. "Optogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Florian Pernin & Qiao-Ling Cui & Abdulshakour Mohammadnia & Milton G. F. Fernandes & Jeffery A. Hall & Myriam Srour & Roy W. R. Dudley & Stephanie E. J. Zandee & Wendy Klement & Alexandre Prat & Hanna, 2024. "Regulation of stress granule formation in human oligodendrocytes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Chen Wang & Hideki Tanizawa & Connor Hill & Aaron Havas & Qiang Zhang & Liping Liao & Xue Hao & Xue Lei & Lu Wang & Hao Nie & Yuan Qi & Bin Tian & Alessandro Gardini & Andrew V. Kossenkov & Aaron Gold, 2024. "METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Marta Vicioso-Mantis & Raquel Fueyo & Claudia Navarro & Sara Cruz-Molina & Wilfred F. J. Ijcken & Elena Rebollo & Álvaro Rada-Iglesias & Marian A. Martínez-Balbás, 2022. "JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Anthony Khong & Tyler Matheny & Thao Ngoc Huynh & Vincent Babl & Roy Parker, 2022. "Limited effects of m6A modification on mRNA partitioning into stress granules," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Hyun Jung Hwang & Tae Lim Park & Hyeong-In Kim & Yeonkyoung Park & Geunhee Kim & Chiyeol Song & Won-Ki Cho & Yoon Ki Kim, 2023. "YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Ziqi Ren & Wei Tang & Luxin Peng & Peng Zou, 2023. "Profiling stress-triggered RNA condensation with photocatalytic proximity labeling," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Meng Xu & Dulmi Senanayaka & Rongwei Zhao & Tafadzwa Chigumira & Astha Tripathi & Jason Tones & Rachel M. Lackner & Anne R. Wondisford & Laurel N. Moneysmith & Alexander Hirschi & Sara Craig & Sahar A, 2024. "TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-19, 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_s41467-023-42650-3. 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.