Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma

Di Yu, Yingying Liang, Claudia Kim, Anbalagan Jaganathan, Donglei Ji, Xinye Han, Xuelan Yang, Yanjie Jia, Ruirui Gu, Chunyu Wang, Qiang Zhang, Ka Lung Cheung, Ming-Ming Zhou () and Lei Zeng ()
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Di Yu: The First Hospital of Jilin University
Yingying Liang: The First Hospital of Jilin University
Claudia Kim: Icahn School of Medicine at Mount Sinai
Anbalagan Jaganathan: Icahn School of Medicine at Mount Sinai
Donglei Ji: The First Hospital of Jilin University
Xinye Han: The First Hospital of Jilin University
Xuelan Yang: The First Hospital of Jilin University
Yanjie Jia: The First Hospital of Jilin University
Ruirui Gu: The First Hospital of Jilin University
Chunyu Wang: Jilin University
Qiang Zhang: The First Hospital of Jilin University
Ka Lung Cheung: Icahn School of Medicine at Mount Sinai
Ming-Ming Zhou: Icahn School of Medicine at Mount Sinai
Lei Zeng: The First Hospital of Jilin University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract BRD4-NUT, a driver fusion mutant in rare and highly aggressive NUT carcinoma, acts in aberrant transcription of anti-differentiation genes by recruiting histone acetyltransferase (HAT) p300 and promoting p300-driven histone hyperacetylation and nuclear condensation in chromatin. However, the molecular basis of how BRD4-NUT recruits and activates p300 remains elusive. Here, we report that BRD4-NUT contains two transactivation domains (TADs) in NUT that bind to the TAZ2 domain in p300. Our NMR structures reveal that NUT TADs adopt amphipathic helices when bound to the four-helical bundle TAZ2 domain. The NUT protein forms liquid-like droplets in-vitro that are enhanced by TAZ2 binding in 1:2 stoichiometry. The TAD/TAZ2 bipartite binding in BRD4-NUT/p300 triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin that comprise histone H3 lysine 27 and 18 acetylation and transcription proteins BRD4L/S, CDK9, MED1, and RNA polymerase II. The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT’s bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.

Date: 2023
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DOI: 10.1038/s41467-023-36063-5

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