TY - JOUR
T1 - Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma
AU - Yu, Di
AU - Liang, Yingying
AU - Kim, Claudia
AU - Jaganathan, Anbalagan
AU - Ji, Donglei
AU - Han, Xinye
AU - Yang, Xuelan
AU - Jia, Yanjie
AU - Gu, Ruirui
AU - Wang, Chunyu
AU - Zhang, Qiang
AU - Cheung, Ka Lung
AU - Zhou, Ming Ming
AU - Zeng, Lei
N1 - Funding Information:
We thank Prof. Jianxin You at University of Pennsylvania Perelman School of Medicine for providing valuable NUT constructs, and Prof. Christopher A. French at Harvard Medical School for NC cell lines, and L. Sun for assistance with microscopy. We thank the State Key Laboratory of Supramolecular Structure and Materials at Jilin University for the use of their research facilities. This work was supported in part by the research fund from the First Hospital of Jilin University (Changchun, China), the Open Project of State Key Laboratory for Supramolecular Structure and Materials, JLU (SKLSSM201602), JLU Science and Technology Innovative Research Team (JLUSTIRT, 2017TD-25), International Center of Future Science, JLU, and National Natural Science Foundation of China (31770780; L.Z.).
Funding Information:
We thank Prof. Jianxin You at University of Pennsylvania Perelman School of Medicine for providing valuable NUT constructs, and Prof. Christopher A. French at Harvard Medical School for NC cell lines, and L. Sun for assistance with microscopy. We thank the State Key Laboratory of Supramolecular Structure and Materials at Jilin University for the use of their research facilities. This work was supported in part by the research fund from the First Hospital of Jilin University (Changchun, China), the Open Project of State Key Laboratory for Supramolecular Structure and Materials, JLU (SKLSSM201602), JLU Science and Technology Innovative Research Team (JLUSTIRT, 2017TD-25), International Center of Future Science, JLU, and National Natural Science Foundation of China (31770780; L.Z.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85146765483&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36063-5
DO - 10.1038/s41467-023-36063-5
M3 - Article
C2 - 36690674
AN - SCOPUS:85146765483
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 378
ER -