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Cited by 5Genomics and Chromatin DynamicsProtein Structure and DynamicsRNA Research and Splicing

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CBP-IDRs regulate acetylation and gene expression

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Gelder, Katie L., Carruthers, Nicola A., Gilbert, Grace, Harrison, Laura J., Evans, Brychan V., Evans, Thomas I., Ball, Sophie S., Dunning, Mark, Craggs, Timothy D., Twelvetrees, Alison E., Bose, Daniel A.·2026·Cell Reports
DOI 10.1016/j.celrep.2026.117109PMC PMC13013760

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Abstract

Intrinsically disordered regions (IDRs) are essential regulators of protein function despite lacking stable secondary and tertiary structures. IDRs are integral to the function of multidomain regulatory proteins, such as the essential transcriptional coactivators cAMP response element-binding protein (CREB)-binding protein (CBP) and EP300 (p300), but how their multiple IDRs work together to regulate function remains poorly understood. Here, we demonstrate that different CBP-IDRs cooperate to control complex nuclear behaviors. We show how CBP-IDRs with different sequence properties make unique contributions to CBP behavior, establishing a critical balance between positive and negative regulation of CBP condensates. These opposing interactions are functionally important, tuning CBP's sensitivity to regulatory cues such as lysine acetylation. Disruption of this balance fundamentally alters CBP's chromatin occupancy, patterns of histone acetylation, and downstream gene expression. Together, our work reveals an unexpected mechanism of intramolecular cooperation between distinct IDRs and highlights how their properties shape the functional landscape of multi-domain proteins.

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Graphical abstract CC BY · PubMed Central
Figure 1 CBP forms fluid-like puncta in the nucleus (A) Immunofluorescence of CBP in HEK293T cells; scale bars, 10 μm. (B–D) CBP-Halo HEK293T cells: (B) western blot, (C) confocal microscopy of CBP-HaloTMR, (D) lattice light-sheet microscopy. Scale bars, 10 μm (C) and 5 μm (D). (E) Dynamic behavior of CBP-HaloTMR condensates (see also Video S1). Boxes indicate enlarged regions. Scale bar, 10 μm. (F and G) FRAP of CBP-HaloJF549 condensates. (F) Confocal microscopy showing FRAP; scale bar, 10 μm. (G) FRAP curves; n = 7 (see also Video S1). (H) CBPWT domain map and predicted disorder. DISOPRED324 (top); PONDR25 (bottom). (I and J) (I) OptoDroplet of CBPIDR6 and CBPIDR7. Boxes indicate enlarged regions. Scale bar, 10 μm. (J) Fold change in SD of gray values. Shading highlights initial 30 s. Bars represent mean ± SEM; n = 3 biological replicates. (K) Initial rate of change calculated over initial 30 s. AL, autoregulatory loop; -ve, Opto-NLS negative control. Bars represent mean ± SEM (ns, not significant); n = 3 biological replicates, p values from unpaired t test. See also Figure S1.
Figure 1 CBP forms fluid-like puncta in the nucleus (A) Immunofluorescence of CBP in HEK293T cells; scale bars, 10 μm. (B–D) CBP-Halo HEK293T cells: (B) western blot, (C) confocal microscopy of CBP-HaloTMR, (D) lattice light-sheet microscopy. Scale bars, 10 μm (C) and 5 μm (D). (E) Dynamic behavior of CBP-HaloTMR condensates (see also Video S1). Boxes indicate enlarged regions. Scale bar, 10 μm. (F and G) FRAP of CBP-HaloJF549 condensates. (F) Confocal microscopy showing FRAP; scale bar, 10 μm. (G) FRAP curves; n = 7 (see also Video S1). (H) CBPWT domain map and predicted disorder. DISOPRED324 (top); PONDR25 (bottom). (I and J) (I) OptoDroplet of CBPIDR6 and CBPIDR7. Boxes indicate enlarged regions. Scale bar, 10 μm. (J) Fold change in SD of gray values. Shading highlights initial 30 s. Bars represent mean ± SEM; n = 3 biological replicates. (K) Initial rate of change calculated over initial 30 s. AL, autoregulatory loop; -ve, Opto-NLS negative control. Bars represent mean ± SEM (ns, not significant); n = 3 biological replicates, p values from unpaired t test. See also Figure S1.CC BY · PubMed Central
Figure 2 CBP-IDRs affect the behavior of full-length CBPWT (A) CBPΔIDR-GFP constructs. (B–F) Confocal microscopy of CBP-GFP condensates in HEK293T. (B) Maximum projection; scale bar, 10 μm. (C) Percentage of nuclei displaying diffuse or punctate signal. (D) SD of gray values. (E) Number of condensates per nucleus. Dashed line shows 6 puncta per nucleus threshold. (F) Integrated intensity density (IID). n = 3 biological replicates; p values by Kruskal-Wallis test. (G and H) FRAP of CBPWT-GFP, CBPΔIDR6-GFP, and CBPΔAL-GFP. (G) Confocal microscopy showing FRAP; scale bar, 10 μm. (H) FRAP curves. Relative fluorescence recovery normalized to pre-bleached intensity for a 90 s time period following bleaching. Gray shading highlights imaging pre-bleach; green line denotes bleaching. Still images from Videos S6, S7, and S8. (I) 1,6-hexanediol treatment; scale bar, 10 μm. See also Videos S3, S4, and S5. (J and K) RNase treatment. (J) Cells were treated with 100 μg/mL RNase A for 20 min; images were taken pre- and post-treatment; scale bars, 5 μm. (K) IID. (L–O) CBPWT-GFP, CBPΔIDR6-GFP, and CBPΔIDR7-GFP showing dominant phase separation phenotype on CBP-HaloJF646 condensates. (L) Lattice light-sheet microscopy; scale bars, 5 μm. (M) Number of condensates per nucleus. Dashed line represents a threshold value of 6 puncta per nuclei. (N) IID. (O) Condensate volume (μm3). Data points highlight individual nuclei. n = 3 biological replicates; p values by Kruskal-Wallis test. See also Figure S2.
Figure 2 CBP-IDRs affect the behavior of full-length CBPWT (A) CBPΔIDR-GFP constructs. (B–F) Confocal microscopy of CBP-GFP condensates in HEK293T. (B) Maximum projection; scale bar, 10 μm. (C) Percentage of nuclei displaying diffuse or punctate signal. (D) SD of gray values. (E) Number of condensates per nucleus. Dashed line shows 6 puncta per nucleus threshold. (F) Integrated intensity density (IID). n = 3 biological replicates; p values by Kruskal-Wallis test. (G and H) FRAP of CBPWT-GFP, CBPΔIDR6-GFP, and CBPΔAL-GFP. (G) Confocal microscopy showing FRAP; scale bar, 10 μm. (H) FRAP curves. Relative fluorescence recovery normalized to pre-bleached intensity for a 90 s time period following bleaching. Gray shading highlights imaging pre-bleach; green line denotes bleaching. Still images from Videos S6, S7, and S8. (I) 1,6-hexanediol treatment; scale bar, 10 μm. See also Videos S3, S4, and S5. (J and K) RNase treatment. (J) Cells were treated with 100 μg/mL RNase A for 20 min; images were taken pre- and post-treatment; scale bars, 5 μm. (K) IID. (L–O) CBPWT-GFP, CBPΔIDR6-GFP, and CBPΔIDR7-GFP showing dominant phase separation phenotype on CBP-HaloJF646 condensates. (L) Lattice light-sheet microscopy; scale bars, 5 μm. (M) Number of condensates per nucleus. Dashed line represents a threshold value of 6 puncta per nuclei. (N) IID. (O) Condensate volume (μm3). Data points highlight individual nuclei. n = 3 biological replicates; p values by Kruskal-Wallis test. See also Figure S2.CC BY · PubMed Central
Figure 3 Sequence properties of CBP-IDRs (A) Sequence properties of CBPWT, CBPCFID, CBPIDR6, and CBPIDR7. Amino acids are grouped by property: polar (Q, N, S, T, G, H, C); proline (P); aliphatic (A, L, M, I, V); charged (E, D, R, K); aromatic (F, Y, W).35 Numbers indicate the fraction of amino acids with each property. (B) Linear amino acid composition35; green bar highlights 18× polyQ. (C) Comparison of the 12 most-enriched or -depleted sequence parameters (relative to all human IDR proteins) in CBPWT and shuffle mutants, using NARDINI+.28,29 Features from main text are highlighted in bold. (D–F) Effect of shuffled IDRs on CBP condensates. (D) Confocal microscopy; scale bars, 10 μm. (E) Number of condensates per nucleus. (F) IID; n = 3 biological replicates. p values by Kruskal-Wallis test. (G) PLAAC analysis37 showing CBPWT, CBPIDR6-shuffle, and CBPIDR7-shuffle. See also Figure S3.
Figure 3 Sequence properties of CBP-IDRs (A) Sequence properties of CBPWT, CBPCFID, CBPIDR6, and CBPIDR7. Amino acids are grouped by property: polar (Q, N, S, T, G, H, C); proline (P); aliphatic (A, L, M, I, V); charged (E, D, R, K); aromatic (F, Y, W).35 Numbers indicate the fraction of amino acids with each property. (B) Linear amino acid composition35; green bar highlights 18× polyQ. (C) Comparison of the 12 most-enriched or -depleted sequence parameters (relative to all human IDR proteins) in CBPWT and shuffle mutants, using NARDINI+.28,29 Features from main text are highlighted in bold. (D–F) Effect of shuffled IDRs on CBP condensates. (D) Confocal microscopy; scale bars, 10 μm. (E) Number of condensates per nucleus. (F) IID; n = 3 biological replicates. p values by Kruskal-Wallis test. (G) PLAAC analysis37 showing CBPWT, CBPIDR6-shuffle, and CBPIDR7-shuffle. See also Figure S3.CC BY · PubMed Central
Figure 4 CBP-IDRs affect response to acetylation (A) Confocal microscopy after 48-h treatment with 0.5 μM A-485; scale bar, 5 μm. (B–D) Effect of A-485 and TSA on CBP condensates. (B) Percentage of nuclei displaying diffuse or punctate signal; (C) Number of condensates per nucleus. (D) IID. Cells were treated with A-485 for 36 h41 and with TSA for 90 min.42n = 3 biological replicates; p values by Kruskal-Wallis test. (E–G) A-485 concentrations affect CBP condensates. (E) Confocal microscopy after 60 min with A-485 (0 μM = DMSO); scale bar, 5 μm. (F) Number of condensates per nucleus. (G) IID; scale, pseudo-log base 10. n = 3 biological replicates; p values by Kruskal-Wallis test. (H–L) CBPAL acetylation. (H) Confocal microscopy; scale bar, 10 μm. (I) Percentage of nuclei displaying diffuse or punctate signal. (J) number of condensates per nucleus. (K) IID (CBPWT-GFP background). (L) IID (CBPΔIDR6-GFP background). n = 3 biological replicates; p values by Kruskal-Wallis test. (M) Inducible CBP-GFP expression. Confocal microscopy of CBP-GFP HEK293T cells treated with doxycycline (Dox) for 48 h. Dox concentrations: CBPWT-GFP, 25 ng/mL−1; CBPΔIDR6-GFP, 5 ng/mL−1; CBPIDR7-GFP, 25 ng/mL−1; scale bar, 10 μm. (N) Acetylation following Dox induction of CBP-GFP. CBP was resolved using 3%–8% Tris-acetate PAGE (loading control: GAPDH). H3K27ac was resolved using 12% Bis-Tris PAGE (loading control: histone H4). (O) Immunoprecipitation HAT assay using recombinant di-nucleosomes. See also Figure S4.
Figure 4 CBP-IDRs affect response to acetylation (A) Confocal microscopy after 48-h treatment with 0.5 μM A-485; scale bar, 5 μm. (B–D) Effect of A-485 and TSA on CBP condensates. (B) Percentage of nuclei displaying diffuse or punctate signal; (C) Number of condensates per nucleus. (D) IID. Cells were treated with A-485 for 36 h41 and with TSA for 90 min.42n = 3 biological replicates; p values by Kruskal-Wallis test. (E–G) A-485 concentrations affect CBP condensates. (E) Confocal microscopy after 60 min with A-485 (0 μM = DMSO); scale bar, 5 μm. (F) Number of condensates per nucleus. (G) IID; scale, pseudo-log base 10. n = 3 biological replicates; p values by Kruskal-Wallis test. (H–L) CBPAL acetylation. (H) Confocal microscopy; scale bar, 10 μm. (I) Percentage of nuclei displaying diffuse or punctate signal. (J) number of condensates per nucleus. (K) IID (CBPWT-GFP background). (L) IID (CBPΔIDR6-GFP background). n = 3 biological replicates; p values by Kruskal-Wallis test. (M) Inducible CBP-GFP expression. Confocal microscopy of CBP-GFP HEK293T cells treated with doxycycline (Dox) for 48 h. Dox concentrations: CBPWT-GFP, 25 ng/mL−1; CBPΔIDR6-GFP, 5 ng/mL−1; CBPIDR7-GFP, 25 ng/mL−1; scale bar, 10 μm. (N) Acetylation following Dox induction of CBP-GFP. CBP was resolved using 3%–8% Tris-acetate PAGE (loading control: GAPDH). H3K27ac was resolved using 12% Bis-Tris PAGE (loading control: histone H4). (O) Immunoprecipitation HAT assay using recombinant di-nucleosomes. See also Figure S4.CC BY · PubMed Central
Figure 5 CBP-IDRs regulate nuclear chromatin association and H3K27ac (A) Overlap between CBP binding sites. CBPWT-Tet3G (purple), CBPWT-GFP (orange), CBPΔIDR6-GFP (light blue), and CBPIDR7-GFP (dark blue). Magenta bar highlights sites common between each dataset. (B) Peak widths of CBP binding sites. p values from Mann-Whitney U test. (C) Distribution of CBP binding sites by genome region. (D) Genome browser views of CBP and GFP ChIP-seq (top) and H3K27ac CUT&RUN (bottom) at the TSC22D3 gene. Solid bars show binding sites identified using MACS2. (E) Peak widths of enriched H3K27ac domains. p values from Mann-Whitney U test. (F and G) Read density enrichment at H3K27ac domains. (F) H3K27ac and (G) CBP-GFP. H3K27ac peaks were randomly downsampled to match the smallest dataset (CBPWT-GFP, 9,213). p values from Mann-Whitney U test. (H and I) Read density enrichment at 4,657 CBP peaks common in all datasets. (H) H3K27ac and (I) CBP-GFP. p values from Mann-Whitney U test. (J) Distribution of common and unique CBP binding sites. (K and L) CBP-GFP enrichment at unique sites. (K) CBP-GFP and (L) H3K27ac. Heatmaps show ±2.5 kb from center of peaks for CBPWT-GFP (3,049 sites), CBPΔIDR6-GFP (13,776 sites), and CBPIDR7-GFP (12,605 sites). (M and N) Enrichment of (M) CBP-GFP and (N) H3K27ac read densities at 2,348,854 GRCh38 cCREs.45p values from Mann-Whitney U test. p values reported as absolute values or ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Boxplots show median (center line) and first and third quartiles (box). Whiskers extend to 1.5× the interquartile range; individual data points represent outliers. See also Figure S5.
Figure 5 CBP-IDRs regulate nuclear chromatin association and H3K27ac (A) Overlap between CBP binding sites. CBPWT-Tet3G (purple), CBPWT-GFP (orange), CBPΔIDR6-GFP (light blue), and CBPIDR7-GFP (dark blue). Magenta bar highlights sites common between each dataset. (B) Peak widths of CBP binding sites. p values from Mann-Whitney U test. (C) Distribution of CBP binding sites by genome region. (D) Genome browser views of CBP and GFP ChIP-seq (top) and H3K27ac CUT&RUN (bottom) at the TSC22D3 gene. Solid bars show binding sites identified using MACS2. (E) Peak widths of enriched H3K27ac domains. p values from Mann-Whitney U test. (F and G) Read density enrichment at H3K27ac domains. (F) H3K27ac and (G) CBP-GFP. H3K27ac peaks were randomly downsampled to match the smallest dataset (CBPWT-GFP, 9,213). p values from Mann-Whitney U test. (H and I) Read density enrichment at 4,657 CBP peaks common in all datasets. (H) H3K27ac and (I) CBP-GFP. p values from Mann-Whitney U test. (J) Distribution of common and unique CBP binding sites. (K and L) CBP-GFP enrichment at unique sites. (K) CBP-GFP and (L) H3K27ac. Heatmaps show ±2.5 kb from center of peaks for CBPWT-GFP (3,049 sites), CBPΔIDR6-GFP (13,776 sites), and CBPIDR7-GFP (12,605 sites). (M and N) Enrichment of (M) CBP-GFP and (N) H3K27ac read densities at 2,348,854 GRCh38 cCREs.45p values from Mann-Whitney U test. p values reported as absolute values or ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Boxplots show median (center line) and first and third quartiles (box). Whiskers extend to 1.5× the interquartile range; individual data points represent outliers. See also Figure S5.CC BY · PubMed Central
Figure 6 CBP-IDRs regulate gene expression profiles (A and B) Differentially expressed genes between (A) CBPWT-GFP and CBPΔIDR6-GFP and (B) CBPWT-GFP and CBPΔIDR7-GFP. Genes showing significant changes in expression (p < 0.001 and log2FC > 3) are highlighted (red points, gene names, and Table S4). HAND1 (bold) is upregulated in both datasets. (C) Genome browser views of GFP ChIP-seq (top) and H3K27ac CUT&RUN (bottom) at the HAND1 gene. Solid bars show identified binding sites. See also Figure S6.
Figure 6 CBP-IDRs regulate gene expression profiles (A and B) Differentially expressed genes between (A) CBPWT-GFP and CBPΔIDR6-GFP and (B) CBPWT-GFP and CBPΔIDR7-GFP. Genes showing significant changes in expression (p < 0.001 and log2FC > 3) are highlighted (red points, gene names, and Table S4). HAND1 (bold) is upregulated in both datasets. (C) Genome browser views of GFP ChIP-seq (top) and H3K27ac CUT&RUN (bottom) at the HAND1 gene. Solid bars show identified binding sites. See also Figure S6.CC BY · PubMed Central
Figure 7 Summary of CBP-IDR functions (A) Summary of how CBP-IDRs regulate condensates, chromatin localization, and histone acetylation. (B) Summary of how CBP-IDRs work with lysine acetylation to control condensate behavior. See also Figure S7.
Figure 7 Summary of CBP-IDR functions (A) Summary of how CBP-IDRs regulate condensates, chromatin localization, and histone acetylation. (B) Summary of how CBP-IDRs work with lysine acetylation to control condensate behavior. See also Figure S7.CC BY · PubMed Central

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Metadata

Authors
Gelder, K. L., Carruthers, N. A., Gilbert, G., Harrison, L. J., Evans, B. V., Evans, T. I., Ball, S. S., Dunning, M., Craggs, T. D., Twelvetrees, A. E., & Bose, D. A.
Affiliations
University of Sheffield (GB)
Corresponding author
Bose, Daniel A.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2026-03
Volume
45
Issue
3
Pages
117109
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2026.117109
PMC
PMC13013760
OpenAlex
W7135046135
Cited by
5
References
4
Citations by year
2026: 2
FWCI
4.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
  • The Royal Society
  • Biotechnology and Biological Sciences Research Council
  • Wellcome Trust
  • UK Research and Innovation Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
intrinsically disordered regions, CREB-binding protein, EP300, lysine acetylation, protein condensates, histone acetylation, chromatin occupancy, gene expression regulation, transcriptional coactivator, multidomain proteins
MeSH terms
Acetylation, Animals, Chromatin, Gene Expression Regulation, Histones, Humans, Protein Binding, E1A-Associated p300 Protein, CREB-Binding Protein, HEK293 Cells, Intrinsically Disordered Proteins

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