Structural insights into p300 regulation and acetylation-dependent genome organisation

Ibrahim, Ziad; Wang, Tao; Destaing, Olivier; Salvi, Nicola; Hoghoughi, Naghmeh; Chabert, Clovis; Rusu, Alexandra; Gao, Jinjun; Feletto, Leonardo; Reynoird, Nicolas; Schalch, Thomas; Zhao, Yingming; Blackledge, Martin; Khochbin, Saadi; Panne, Daniel

doi:10.6082/syhxt-hep11

Published December 15, 2022 | Version v1

Journal article Open

Structural insights into p300 regulation and acetylation-dependent genome organisation

1. St. Jude Children's Research Hospital
2. Université Grenoble Alpes
3. University of Leicester
4. University of Chicago

Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.

Data availability

All data and materials generated during this investigation are available upon reasonable request to the corresponding author. Chemical shifts for NUT are available from the BMRB under accession ID 51611. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD038798. Source data are provided with this paper.

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