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RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation

Abstract

The bromodomain and extra-terminal motif (BET) protein BRD4 binds to acetylated histones at enhancers and promoters via its bromodomains (BDs) to regulate transcriptional elongation. In human colorectal cancer cells, we found that BRD4 was recruited to enhancers that were co-occupied by mutant p53 and supported the synthesis of enhancer-directed transcripts (eRNAs) in response to chronic immune signaling. BRD4 selectively associated with eRNAs that were produced from BRD4-bound enhancers. Using biochemical and biophysical methods, we found that BRD4 BDs function cooperatively as docking sites for eRNAs and that the BDs of BRD2, BRD3, BRDT, BRG1, and BRD7 directly interact with eRNAs. BRD4-eRNA interactions increased BRD4 binding to acetylated histones in vitro and augmented BRD4 enhancer recruitment and transcriptional cofactor activities. Our results suggest a mechanism by which eRNAs are directly involved in gene regulation by modulating enhancer interactions and transcriptional functions of BRD4.

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Fig. 1: BRD4 co-occupies and regulates mutp53-bound enhancers in response to chronic TNF-α signaling.
Fig. 2: BRD4 associates with RNAs synthesized from genomic regions occupied by BRD4.
Fig. 3: BRD4 directly interacts with eRNAs through its tandem bromodomains.
Fig. 4: eRNAs cooperate with acetylated histones to enhance BRD4 binding in vitro.
Fig. 5: BRD4 enhancer occupancy and the regulation of select eRNAs and genes are modulated by BRD4 interactions with eRNAs.
Fig. 6: Proposed model for eRNA-mediated BRD4 tethering to acetylated histones at active enhancers.

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Acknowledgements

We are grateful to C.-M. Chiang (University of Texas Southwestern) for providing the pF:hBRD4 (1–722)-11d, pcDNA3-F:hBRD4 FL, and pcDNA3-F:hBRD4 ∆BD1/2 plasmids and the BRD4-FL- and BRD4 ∆BD1/2–expressing baculovirus. We are also thankful to X. Chen (University of California, Davis) for providing the SW480 shLacZ and shp53 cell lines. H.R. was supported by the University of California at San Diego Cellular and Molecular Genetics Training Program through an institutional grant from the National Institute of General Medicine (T32 GM007240). This work was supported by Research Scholar Award from the Sidney Kimmel Foundation for Cancer Research 857A6A (S.M.L.), American Cancer Society ACS-IRG 70-002 (S.M.L.), and the University of California Cancer Research Coordinating Committee, CRN-17-420616 (S.M.L.).

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H.R., J.L., Z.S., and S.M.L. conceived the project. H.R., J.L., Z.S., H.L., K.M.R., E.A.K., and S.M.L. devised the methodology. H.R., J.L., Z.S., H.L., K.M.R., and S.M.L. carried out the experiments. H.R., J.L., H.L., Z.S., E.A.K., and S.M.L. analyzed the data. H.R., J.L., and S.M.L. wrote the original draft of the manuscript. H.R., J.L., E.A.K., and S.M.L. reviewed and edited the manuscript. S.M.L. acquired the necessary funding for and supervised this project.

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Correspondence to Shannon M. Lauberth.

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Supplementary Figure 1 BRD4 cooperates with mutp53 at active enhancers upon chronic immune signaling.

a, Venn diagram depicting the overlap between p53R273H,P309S and BRD4 binding at H3K27ac- and H3K4me1-enriched, intergenic regions in SW480 cells after 16 h of TNF-α treatment. b, De novo motif analyses of BRD4 and p53R273H, P309S co-bound ChIP-seq peaks at active enhancers. c, Sequential ChIP–qPCR with p53 immunoprecipitation followed by BRD4 or IgG immunoprecipitation in SW480 cells after 16 h of TNF-α treatment, at enhancer (A) and nonspecific (B) regions of MMP9 and CCL2. d, Immunoblot analysis of BRD4 coimmunoprecipitation with lysates from SW480 cells treated with TNF-α for 0 or 16 h. e, Immunoblot analysis of BRD4 and p53 (wild type and R273H) interactions (top) using recombinant proteins analyzed by Coomassie staining (bottom). n = 3 independent coimmunoprecipitation and binding assays. f, Immunoblot analysis of SW480 cells expressing LacZ (Ctrl) or p53 shRNA and treated with TNF-α for 0 or 16 h. g, qRT–PCR analysis of MMP9 and CCL2 eRNAs and mRNAs in SW480 cells expressing control (Ctrl) or BRD4 shRNA (BRD4-2) and treated with TNF-α for 0 or 16 h. h, ChIP–qPCR of IgG and p53R273H,P309S enrichment at enhancer (A) and nonspecific (B) regions of MMP9 and CCL2 in SW480 cells expressing Ctrl or BRD4 shRNA and treated with TNF-α for 0 or 16 h. i, Immunoblot and qRT–PCR analysis of SW480 cells treated with vehicle or JQ1 and with TNF-α for 0 or 16 h. In g and i, expression levels following TNF-α treatment are relative to the levels before treatment and data represent the mean and s.e.m. of n= 3 independent experiments. In c and h, data represent the mean and s.e.m. of n = 2 independent experiments that are representative of three replicates. Statistical significance was determined by two-tailed Student’s t test. *P < 0.05

Supplementary Figure 2 BRD4 directly interacts with RNAs.

a, qRT–PCR and immunoblot analyses of SW480 cells treated with TNF-α for 0 or 16 h. b, qRT–PCR analysis of the CSF2 and TNFAIP3 eRNAs following UV-RIP using IgG or BRD4 antibodies in SW480 cells treated with TNF-α for 0 or 16 h. Enrichment levels for each TNF-α-treated immunoprecipitation are relative to the levels before TNF-α treatment. In a and b, data represent the mean and s.e.m. of n = 3 independent experiments. Statistical significance was determined by two-tailed Student’s t test. *P < 0.05. c, UCSC Genome Browser images of GRO-seq and BRD4 ChIP-seq signals in SW480 cells treated as described in a at active enhancer regions of CSF2 and TNFAIP3. d, SYBR Gold staining of an in vitro binding assay between BRD4-FL and various in vitro–transcribed RNA molecules. n = 3 independent experiments. e, Quantification of RNA EMSAs to determine the fraction of RNA bound to BRD4-FL as shown in Fig. 3a and BRD4 ΔBD1/2 as shown in Fig. 3e

Supplementary Figure 3 eRNAs enhance BRD4 binding to acetylated histone peptides and octamers in vitro.

a, Recombinant FLAG-p300 protein analyzed by Coomassie staining. b, Immobilized peptide pulldown assay using biotinylated H4 peptides (unmodified or K16 acetylated) with either recombinant BRD4-FL or BRD4 ΔBD1/2 in the absence or presence of refolded CCL2 eRNA as indicated. Recombinant BRD4-FL and BRD4 ΔBD1/2 were detected by immunoblotting with an antibody specific to BRD4. c, Immunoblot analysis of in vitro binding assays with unacetylated or acetylated histone octamers, recombinant BRD4-FL or ΔBD1/2, and refolded CCL2 eRNA as indicated. d, In vitro histone octamer binding assay as described in c with recombinant BRD4-FL and increasing doses of refolded MMP9 eRNA (0.06, 0.1, 0.2, 1, and 2 nM). In c and d, immunoblot analysis with H3K27ac and H3K9ac antibodies confirmed p300/acetyl-CoA-mediated acetylation of histone octamers. Lower panels in bd represent the loading of the indicated proteins by Coomassie staining. n = 3 independent experiments for all in vitro binding assays

Supplementary Figure 4 eRNA depletion reduces the expression of corresponding mRNAs and impacts BRD4 binding.

a, qRT–PCR analysis of MMP9 and CCL2 eRNAs and mRNAs in SW480 cells expressing control or a second shRNA oligonucleotide against MMP9 and CCL2 eRNAs and treated with TNF-α for 0 or 16 h. b, qRT–PCR analysis of CPA4 and CYP24A1 eRNAs and mRNAs in SW480 cells treated as described in Fig. 5a. c,d, Immunoblot (c) and qRT–PCR analysis (d) of SW480 cells treated with TNF-α for 0 or 16 h and treated with Act D for 2 h. In a, b, and d, the expression levels following TNF-α treatment are relative to the levels before TNF-α exposure and data represent the mean and s.e.m. of n = 3 independent experiments. e, ChIP–qPCR analyses of IgG and BRD4 enrichment in SW480 cells treated as described in d, at the enhancer (A) and nonspecific (B) regions of the MMP9 and CCL2 gene loci. Data represent the mean and s.e.m. of n = 2 independent ChIP experiments that are representative of at least three replicates. Statistical significance was determined by two-tailed Student’s t test. *P < 0.05

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Rahnamoun, H., Lee, J., Sun, Z. et al. RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation. Nat Struct Mol Biol 25, 687–697 (2018). https://doi.org/10.1038/s41594-018-0102-0

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