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A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing

Author

Listed:
  • Cui Liu

    (University of North Carolina
    Present address: Novozymes (China) Investment Co. Ltd., Beijing 100085, China (C.L.))

  • Yanbao Yu

    (University of North Carolina
    Present address: The J. Craig Venter Institute, 9704 Medical Center Drive, Rockville, Maryland 20850, USA (Y.Y.))

  • Feng Liu

    (Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina)

  • Xin Wei

    (University of North Carolina)

  • John A. Wrobel

    (University of North Carolina)

  • Harsha P. Gunawardena

    (University of North Carolina)

  • Li Zhou

    (University of North Carolina)

  • Jian Jin

    (Icahn School of Medicine at Mount Sinai)

  • Xian Chen

    (University of North Carolina
    Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina
    Fudan University)

Abstract

Immune cells develop endotoxin tolerance (ET) after prolonged stimulation. ET increases the level of a repression mark H3K9me2 in the transcriptionally silent chromatin specifically associated with pro-inflammatory genes. However, it is not clear what proteins are functionally involved in this process. Here we show that a novel chromatin activity-based chemoproteomic (ChaC) approach can dissect the functional chromatin protein complexes that regulate ET-associated inflammation. Using UNC0638 that binds the enzymatically active H3K9-specific methyltransferase G9a/GLP, ChaC reveals that G9a is constitutively active at a G9a-dependent mega-dalton repressome in primary endotoxin-tolerant macrophages. G9a/GLP broadly impacts the ET-specific reprogramming of the histone code landscape, chromatin remodelling and the activities of select transcription factors. We discover that the G9a-dependent epigenetic environment promotes the transcriptional repression activity of c-Myc for gene-specific co-regulation of chronic inflammation. ChaC may also be applicable to dissect other functional protein complexes in the context of phenotypic chromatin architectures.

Suggested Citation

  • Cui Liu & Yanbao Yu & Feng Liu & Xin Wei & John A. Wrobel & Harsha P. Gunawardena & Li Zhou & Jian Jin & Xian Chen, 2014. "A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing," Nature Communications, Nature, vol. 5(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6733
    DOI: 10.1038/ncomms6733
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    Cited by:

    1. Maxine S. Y. Lam & Jose Antonio Reales-Calderon & Jin Rong Ow & Joey J. Y. Aw & Damien Tan & Ragavi Vijayakumar & Erica Ceccarello & Tommaso Tabaglio & Yan Ting Lim & Wang Loo Chien & Fritz Lai & Anth, 2023. "G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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