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

Homa Rahnamoun; Jihoon Lee; Zhengxi Sun; Hanbin Lu; Kristen M. Ramsey; Elizabeth A. Komives; Shannon M. Lauberth

doi:10.1038/s41594-018-0102-0

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

Homa Rahnamoun, Jihoon Lee, Zhengxi Sun, Hanbin Lu, Kristen M. Ramsey, Elizabeth A. Komives, Shannon M. Lauberth^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

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.

Original language	English (US)
Pages (from-to)	687-697
Number of pages	11
Journal	Nature Structural and Molecular Biology
Volume	25
Issue number	8
DOIs	https://doi.org/10.1038/s41594-018-0102-0
State	Published - Aug 1 2018

Funding

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.).

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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@article{0481553fb3a64511978338eaf56c5ed0,

title = "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.",

author = "Homa Rahnamoun and Jihoon Lee and Zhengxi Sun and Hanbin Lu and Ramsey, {Kristen M.} and Komives, {Elizabeth A.} and Lauberth, {Shannon M.}",

note = "Funding Information: 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.). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41594-018-0102-0",

language = "English (US)",

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T1 - RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation

AU - Rahnamoun, Homa

AU - Lee, Jihoon

AU - Sun, Zhengxi

AU - Lu, Hanbin

AU - Ramsey, Kristen M.

AU - Komives, Elizabeth A.

AU - Lauberth, Shannon M.

N1 - Funding Information: 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.). Publisher Copyright: © 2018, The Author(s).

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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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U2 - 10.1038/s41594-018-0102-0

DO - 10.1038/s41594-018-0102-0

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SN - 1545-9993

VL - 25

SP - 687

EP - 697

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 8

ER -

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

Abstract

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