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

Cui Liu, Yanbao Yu, Feng Liu, Xin Wei, John A. Wrobel, Harsha P. Gunawardena, Li Zhou, Jian Jin and Xian Chen ()
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Cui Liu: University of North Carolina
Yanbao Yu: University of North Carolina
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

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6733

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