Structural insights into p300 regulation and acetylation-dependent genome organisation

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

doi:10.1038/s41467-022-35375-2

Cited by 32 publications

(21 citation statements)

References 175 publications

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“…Consistent with the notion that CBP/p300 play important roles in Aire targeting to active loci, both degrader dCBP-1 and catalytic inhibitor A-485 impaired Aire binding to SEs (Figures 3F and 3G). This suggests that Aire may preferentially home in on the catalytically active form of CBP/p300 that often form clusters and accumulate at active genetic loci 2,59,60 .…”

Section: Resultsmentioning

confidence: 99%

Mechanism for controlled assembly of transcriptional condensates by Aire

Huoh,

Zhang,

Torner

et al. 2023

Preprint

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Transcriptional hubs have emerged as critical structural components in gene expression and regulation. Studies on hub assembly have primarily focused on the concept of phase separation of disordered regions within transcriptional regulators (TRs). We here introduce an unexplored mode of hub assembly by investigating the Autoimmune regulator (Aire), an indispensable TR in immune homeostasis distinguished by its unique capacity to form homopolymers. We demonstrate that Aire forms active transcriptional hubs connecting disparate inter-chromosomal genomic loci, and that this hub assembly relies on both Aire's polymerizing domain CARD and the transcriptional activation domain (TAD). In a departure from the conventional TAD functions, Aire's TAD orchestrates site-specific hub assembly by coupling CARD polymerization with genomic targeting. Through direct interactions with the co-activators CBP/p300, Aire TAD guides Aire to genomic loci enriched with CBP/p300, where CARD polymerization is initiated. To avert unwanted CARD polymerization at inappropriate sites, Aire employs its chromatin reader domain PHD1 to disperse Aire outside of its target sites and confine Aire polymerization to CBP/p300-rich loci. Our work thus reveals previously unrecognized mechanism by which a TAD and a chromatin reader domain collaborate to discern genomic loci and facilitate TR polymerization, unveiling a multi-layered assembly process for transcriptional hubs.

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Section: Resultsmentioning

confidence: 99%

Mechanism for controlled assembly of transcriptional condensates by Aire

Huoh,

Zhang,

Torner

et al. 2023

Preprint

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“…During the course of this study, two studies reported that the BRD4-NUT fusion protein contains two TADs in NUT that bind to TAZ2, and the TAD-TAZ interaction triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin 35,36 . Ibrahim et al showed that in vitro, the NUT TADs stimulate autoacetylation of the p300s fragment (aa324-2094), but not a shorter p300 fragment (aa1048-1664) 36 .…”

Section: Cells With Taz2 Truncations Are Vulnerable To Hdac Inhibitorsmentioning

confidence: 97%

TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition

Xu,

Xuan,

et al. 2023

Nat Commun

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The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a ‘closed’ state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that ‘opens’ the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations.

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“…Somatic expression of NUTM1 protein is problematic because its normal function is to hyperacetylate histones for their removal during spermatogenesis (Shiota et al 2018, Rousseaux et al 2022). Thus, it is a powerful attractor and facilitator of the p300/CBP histone acetyltransferases (Wang and You 2015, Ibrahim et al 2022, Yu et al 2023.…”

Section: Introductionmentioning

confidence: 99%

Cell state-dependent chromatin targeting in NUT carcinoma

Kuroda

Alekseyenko

Zee

et al. 2023

Preprint

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Aberrant transcriptional programming and chromatin dysregulation are common to most cancers. Whether by deranged cell signaling or environmental insult, the resulting oncogenic phenotype is typically manifested in transcriptional changes characteristic of undifferentiated cell growth. Here we analyze targeting of an oncogenic fusion protein, BRD4-NUT, composed of two normally independent chromatin regulators. The fusion causes the formation of large hyperacetylated genomic regions or megadomains, mis-regulation ofc-MYC, and an aggressive carcinoma of squamous cell origin. Our previous work revealed largely distinct megadomain locations in different NUT carcinoma patient cell lines. To assess whether this was due to variations in individual genome sequences or epigenetic cell state, we expressed BRD4-NUT in a human stem cell model and found that megadomains formed in dissimilar patterns when comparing cells in the pluripotent state with the same cell line following induction along a mesodermal lineage. Thus, our work implicates initial cell state as the critical factor in the locations of BRD4-NUT megadomains. These results, together with our analysis of c-MYC protein-protein interactions in a patient cell line, are consistent with a cascade of chromatin misregulation underlying NUT carcinoma.

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Structural insights into p300 regulation and acetylation-dependent genome organisation

Cited by 32 publications

References 175 publications

Mechanism for controlled assembly of transcriptional condensates by Aire

Mechanism for controlled assembly of transcriptional condensates by Aire

TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition

Cell state-dependent chromatin targeting in NUT carcinoma

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