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Transcription factor dimerization activates the p300 acetyltransferase


The transcriptional co-activator p300 is a histone acetyltransferase (HAT) that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using two model transcription factors, IRF3 and STAT1, we demonstrate that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation. We describe a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighbouring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling and the activation and dimerization of transcription factors control the activation of p300, and therefore explain why gene transcription is associated with chromatin acetylation.

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Fig. 1: Transcription factor dimerization activates p300.
Fig. 2: The structure of p300 adopts a AIL-swap conformation.
Fig. 3: Structural rearrangement of the RING domain.
Fig. 4: Regulation of HAT activity by flanking domains.
Fig. 5: Acetylation of the AIL regulates dynamic interaction with the substrate-binding pocket of p300.

Data availability

Coordinates for the p300 core structure and BΔRP bound to a diacetylated histone H4 peptide are available from the Protein Data Bank (PDB) under accession numbers 6GYR and 6GYT, respectively. Source data are available for Fig. 1b, f and Extended Data Fig. 1d. Figure 1d shows the initial velocities from reactions shown in Extended Data Fig. 1d.


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This work was supported by grant 16-0280 from Worldwide Cancer Research. E.O. was supported by an EMBL Interdisciplinary Postdoctoral (EIPOD) fellowship. S.R. was supported by the Fondation ARC pour la recherche sur le Cancer and by the Fondation FINOVI. A.S.H. is a postdoctoral fellow in the laboratory of R.V. Pappu at Washington University in St. Louis. The computational work was supported by the Human Frontiers Science Program (grant RGP0034/2017 to R.V. Pappu) and the St Jude Collaborative Research Consortium on Membraneless Organelles (to R.V. Pappu). We thank the staff at the European Synchrotron Radiation Facility (ESRF) beamlines ID29; L. Signor for mass spectroscopy analysis; R. Vance for the plasmid encoding GST-STING; and P. Cole for the A-485 inhibitor. S.K. and D.P. were supported by ANR Episperm3 program. S.K. received additional support from Fondation ARC Canc’air project (RAC16042CLA), Plan Cancer (CH7-INS15B66 and ASC16012CSA) and the Université Grenoble Alpes ANR-15-IDEX-02 LIFE and IDEX SYMER.

Reviewer information

Nature thanks L. Chen, V. Hilser and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations



E.O. designed and performed most experiments, analysed and validated the data and revised the draft with assistance from S.R., Z.I., N.H. and J.G. A.S.H. performed computational modelling and revised the draft. S.K. provided supervision, funding acquisition and commented on the draft. D.P. was involved in conceptualization, supervision, project administration, funding acquisition and wrote the original and revised drafts.

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Correspondence to Daniel Panne.

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Extended data figures and tables

Extended Data Fig. 1 The effect of IRF3 or STAT1 activation and oligomerization on p300 autoacetylation.

a, The domain structure of IRF3. The truncation construct used is shown at the bottom. b, Size-exclusion chromatography of IRF3 variants. Red, unphosphorylated IRF3; blue, phosphorylated pIRF3; green, C-terminally truncated IRF3ΔC. Representative data of three independent experiments are shown. c, A constant amount of p300s (2 μM) was incubated alone or in the presence of C-terminally truncated IRF3ΔC (2 μM) for the indicated time points. Samples were analysed by SDS–PAGE followed by Coomassie staining and autoradiography. d, Progress curves of HAT scintillation proximity assay. Histone H4 substrate acetylation in the presence (green) or absence (black) of pIRF3 and varying concentrations of [3H]acetyl-CoA. The degree of histone H4 substrate acetylation at different time points and the initial velocity (cpm min−1) at the indicated acetyl-CoA concentrations were determined and plotted in Fig. 1e. Three independent experiments were performed and the mean value and error bars representing the standard deviation are shown. e, The domain structure of STAT1. The truncation constructs used are shown at the bottom, and the Tyr701 phosphorylation site is indicated. f, Uncropped images of SDS–PAGE gels shown in Fig. 1d. The 14C autoacetylation signal of p300s is shown at the bottom. g, Size-exclusion chromatography of STAT1 variants. Black, STAT1ΔNC; green, STAT1ΔN; red, Y701-phosphorylated pSTAT1ΔNC; blue, Y701-phosphorylated pSTAT1ΔN. h, SDS–PAGE analysis of STAT1 variants and analysis by western blotting. Top, Coomassie staining of SDS–PAGE gel; middle, PonceauS staining; bottom, western blot using anti-Phospho-Stat1 (Tyr701). Representative data of three independent experiments are shown. For gel source data, see Supplementary Fig. 1.

Source data

Extended Data Fig. 2 Crystal packing of the p300 core molecule.

a, There are four p300 molecules (monomers I–IV) in the asymmetric crystallographic unit. The four molecules show an antiparallel arrangement of the BRP-HAT domains. As a result, HAT domains from monomers I and II are closely apposed. Monomers III and IV engage monomer IVsym and monomer IIIsym, respectively, of a neighbouring crystallographic unit, showing that all promoters are in a AIL loop-swap conformation. Black arrows indicate the direction of the AIL. The disordered segment of the AIL is shown as a black dotted line. b, c, Electron density of the AIL. 2FoFc (b) and FoFc (c) difference density omit maps contoured at 0.8 and 2.0 r.m.s.d., respectively. Coloured as in Fig. 3.

Extended Data Fig. 3 Structural analysis of the RING domains.

a, Superposition of the four p300 molecules (monomers I–IV) in the asymmetric crystallographic unit. Whereas the bromodomains (Bd), PHD and HAT domains superpose with a r.m.s.d. of approximately 0.9 Å, the RING domains adopt multiple conformations. b, 2FoFc (blue mesh) and anomalous difference Fourier maps (orange mesh) for the four RING domains contoured around 1σ and 2.5σ, respectively.

Extended Data Fig. 4 Regulation of HAT activity by flanking domains.

a, The domain structure of p300. Sequence conservation of the AIL is shown using WebLogo54. The constructs used are shown. b, Analysis of in vitro expression of the indicated p300 variants. Purified proteins were analysed for autoacetylation by immunoblotting with anti-p300(K1499ac) antibody (left), anti-Flag antibody (middle) and Coomassie staining (right). Representative data of three independent experiments are shown. c, Representative mass spectrometric analysis of BRP_HAT_ZZ_ΔΑΙL after in vitro expression (red) and after SIRT2 mediated deacetylation (black).

Extended Data Fig. 5 Regulation of HAT activity by flanking domains.

a, The AIL contributes to histone substrate acetylation of activated p300. The details of the constructs used are indicated in Extended Data Fig. 4. Defined amounts of p300 variants were incubated with acetyl-CoA and the indicated histones before SDS–PAGE analysis, followed by Coomassie staining and western blotting with the indicated antibodies. b, The indicated amounts of purified p300s variants were incubated with histone octamers as in a, followed by SDS–PAGE and immunoblot analysis with the indicated antibodies. Anti-Kac, pan-acetyl-lysine antibody. Representative data of three independent experiments are shown. c, Crystal structure of the H4(K12ac/K16ac) peptide bound to the BΔRP module containing an in-frame RING deletion. Amino acid residues 1169–1241 were replaced by a single glycine residue. The deletion removes the RING domain (black arrow) and does not adversely affect the structural integrity of the BΔRP module. d, e, Indicated variants of p300 were co-expressed with p53 in H1299 cells and analysed by immunofluorescence with the indicated antibodies (d) or by western blotting (e). Representative data of three independent experiments are shown. Scale bars, 10 μm.

Extended Data Fig. 6 Autoacetylation changes the hydrodynamic properties of p300.

a, Simulations of the AIL in the context of the loop-swapped dimer. Left, cartoon of the trajectory of the AIL (dashed line). Right, representative conformations with the AIL Cα backbone atoms are coloured according to charge. b, SEC–MALLS analysis of deacetylated (blue) and acetylated (yellow) p300 core. Note the decrease in elution volume upon acetylation. c, SEC-MALLS analysis of deacetylated (blue), acetylated (red) BRP_HAT_CH3 and deacetylated (black) and acetylated (green) BRP_HAT_CH3 ΔAIL. There is no increase in elution volume upon acetylation of the ΔAIL construct. d, Comparison of acetylated and deacetylated BRP_HAT and BRP_HAT_CH3. The deacetylated BRP_HAT (green) and deacetylated BRP_HAT_CH3 (blue) elute at the same position, which is indicative of a similar hydrodynamic radius. The acetylated BRP_HAT (yellow) and BRP_HAT_CH3 (red) elute at a larger elution volume. The normalized refractive index is plotted as a function of elution volume from an S200 column coupled to a MALLS detector. Calculated molecular masses are plotted as a function of volume for each eluted peak. The experiment was carried out at least three times with similar results. One representative example of each sample is shown. e, Mass spectrometry analysis (electrospray ionization) of the BRP_HAT before (blue) and after (yellow) autoacetylation. The molecular mass and the number of acetylation events are indicated. f, Mass spectrometry analysis of BRP_HAT_CH3 before (blue) and after (red) autoacetylation. g, Mass spectrometry analysis of BRP_HAT_CH3_ΔΑΙL before (black) and after (green) autoacetylation.

Extended Data Fig. 7 Molecular model and controls showing that p300 acetyltransferase activity is not stimulated by eRNA.

a, p300 is maintained in the inactive state by deacetylases such as SIRT2. IRF3 is autoinhibited by a C-terminal segment in the IAD domain. b, TBK1 phosphorylation activates and dimerizes IRF3. The activated IRF3 dimer engages the IBID domain of p300. c, Recruitment of two molecules of p300 results in trans-autoacetylation in the AIL loop and HAT activation. d, Activated p300 can acetylate chromatin and engage acetylated substrates via the bromodomain. e, A constant amount of p300s (2 μM) was incubated in [14C]acetyl-CoA alone or in the presence of 2 μM Klf6 eRNA for the indicated time points. Samples were analysed by SDS–PAGE followed by Coomassie staining (top) and autoradiography (bottom). f, As in e but in the presence of 0.5 mM EDTA. The experiment was carried out at least twice with consistency. One representative example is shown. g, Quality control of Klf6 RNA. 3 μg Klf6 was deposited on a 1% agarose gel or a 14% 6 M urea PAGE gel and detected by SYBR Safe stain. M, 100-bp DNA ladder.

Extended Data Table 1 Data collection, phasing and refinement statistics
Extended Data Table 2 Thermodynamic analysis of the interaction between p300 BRP and histone peptides by ITC
Extended Data Table 3 Summary of SEC-MALLS and mass spectrometry experiments

Supplementary information

Supplementary Information

This file contains the uncropped gels.

Reporting Summary

Video 1: Simulations of the deacetylated AIL.

All backbone and side chain dihedral angles in the AIL were fully sampled using all-atom Monte Carlo Simulations. Normalized distances between pairs of amino acids of the AIL and the p300 core were plotted in Fig. 5a.

Video 2: Simulations of the acetylated AIL.

Distances between pairs of amino acids of the AIL and the p300 core were plotted in Fig. 5b. After acetylation, lysine-mediated electrostatic interactions are lost.

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Ortega, E., Rengachari, S., Ibrahim, Z. et al. Transcription factor dimerization activates the p300 acetyltransferase. Nature 562, 538–544 (2018).

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  • IFN Regulatory Factor (IRF3)
  • RING Domain
  • Chromatin Acetylation
  • Stimulator Of Interferon Genes (STING)
  • IRF3 Activation

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