The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure
Open accessAbstract
Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“BET inhibition exerted a strong protective effect on left ventricular ejection fraction (Fig. 1B)4,6-10.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“As BET proteins are transcriptional co-activators and their inhibition is associated with protection in heart failure models6-8”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [6]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
Rockman, H. A., Ross, R. S., Harris, A. N., Knowlton, K. U., Steinhelper, M. E., Field, L. J., Ross, J., & Chien, K. R. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.18.8277 · Cited by 807 · cited 1×
“model of cardiac pressure overload, which provides focal hemodynamic stress to the heart and recapitulates several cardinal aspects of pathologic hypertrophy and HF in humans (Rockman et al., 1991).”
RetractedSubramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · cited 1×
“Using gene set enrichment analysis (GSEA) (Subramanian et al., 2005), we compared our set of TAC-induc-”
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B., & Castelli, W. P. (1990) · New England Journal of Medicine · doi:10.1056/nejm199005313222203 · Cited by 5,699 · cited 1×
“The pathologic nature of this process has been validated in large epidemiologic studies, which demonstrate that the presence of chronic cardiac hypertrophy is a robust predictor of subsequent HF and death (Hill and Olson, 2008; Levy et al., 1990).”
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262 · cited 4×
“We and others have utilized this chemical genetic tool to probe BET function in a number of developmental and disease contexts, such as cancer (Delmore et al., 2011; Filippakopoulos et al., 2010), HIV infection (Banerjee et al.”
InfluentialSelf-citationSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961 · cited 3×
“Furthermore, the very recent discovery of asymmetrically loaded BRD4 on a critical subset of state-specific enhancers termed superenhancers (Lovén et al., 2013) raises the possibility that such superenhancers might also be active in the stressed myocardium and contribute to BET target specificity.”
Self-citationBET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.017 · Cited by 2,888 · cited 4×
“Prior studies from our laboratory and others have implicated BET bromodomains in neoplastic MYC transcription in hematopoietic tumors (Delmore et al., 2011; Zuber et al., 2011).”
InfluentialSelf-citationXie, X., Lu, J., Kulbokas, E. J., Golub, T. R., Mootha, V., Lindblad-Toh, K., Lander, E. S., & Kellis, M. (2005) · Nature · doi:10.1038/nature03441 · Cited by 1,872 · cited 1×
“Specifically, we studied the Broad Institute Molecular Signatures Database C3 motif gene sets (Xie et al., 2005), as well as three functional, in vivo signatures of CMspecific transcriptional effectors: Calcineurin-NFAT (Bousette et al.”
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., et al. (2011) · Nature · doi:10.1038/nature10334 · Cited by 1,870 · cited 2×
“Prior studies from our laboratory and others have implicated BET bromodomains in neoplastic MYC transcription in hematopoietic tumors (Delmore et al., 2011; Zuber et al., 2011).”
Self-citation
Cited by
Sorted by citations
Items 101–200 of 417
BET Bromodomain Blockade Mitigates Intimal Hyperplasia in Rat Carotid Arteries
Wang, B., Zhang, M., Takayama, T., Shi, X., Roenneburg, D. A., Kent, K. C., & Guo, L. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.09.045 · Cited by 64
“Super-enhancers are found to be associated with BRD4 at overactive genes in several pathologies, e.g. cancer progression (Whyte et al., 2013; Loven et al., 2013), EC activation (Brown et al., 2014), and cardiomyocyte hypertrophy (Anand et al., 2013).”
BackgroundInfluentialThe chromatin-binding protein Smyd1 restricts adult mammalian heart growth
Franklin, S., Kimball, T. H., Rasmussen, T. L., Rosa‐Garrido, M., Chen, H., Tran, T., Miller, M. R., Gray, R., Jiang, S., Ren, S. V., et al. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00235.2016 · Cited by 63
“Previous investigations have shown unequivocally that chromatin modification can induce hypertrophic growth, as well as restrict it, including in physiological and pathological conditions (3, 4, 15, 23, 36, 50).”
BackgroundKnight, W. E., Cao, Y., Lin, Y.-H., Chi, C., Bai, B., Sparagna, G. C., Zhao, Y., Du, Y., Londono, P., Reisz, J. A., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.01.018 · Cited by 68
Zheng, Z., Xia, L., Hu, G.-S., Liu, J., Hu, Y.-H., Chen, Y.-J., Jia-yin, P., Zhang, W., & Liu, W. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac778 · Cited by 62
“BRD4, a member of the bromodomain and extra-terminal (BET) family of proteins, has been shown to play critical roles in human diseases, such as cancer (7,8), cardiovascular disease (9,10), inflammatory disease (11) and central neural system (CNS) disorders (12).”
BackgroundMumby, S. E., Gambaryan, N., Meng, C., Perros, F., Humbert, M. J. C., Wort, S. J., & Adcock, I. M. (2016) · Respirology · doi:10.1111/resp.12872 · Cited by 62
General mechanism of JQ1 in inhibiting various types of cancer
Jiang, G., Deng, W., Liu, Y., & Wang, C. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.10927 · Cited by 62
Targeting bromodomain and extraterminal proteins in breast cancer
Sahni, J. M., & Keri, R. A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.11.015 · Cited by 61
“BET proteins are involved in various diseases, including inflamation, viral infection, heart failure, and cancer [77,78].”
BackgroundFibroblasts orchestrate cellular crosstalk in the heart through the ECM
Bowers, S., Meng, Q., & Molkentin, J. D. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00043-7 · Cited by 61
Huang, M., Qiu, Q., Xiao, Y., Zeng, S., Zhan, M., Shi, M., Zou, Y., Ye, Y., Liang, L., Yang, X., et al. (2016) · Scientific Reports · doi:10.1038/srep23770 · Cited by 58
BRD4 inhibition for the treatment of pathological organ fibrosis
Stratton, M. S., Haldar, S. M., & McKinsey, T. A. (2017) · F1000Research · doi:10.12688/f1000research.11339.1 · Cited by 58
“We previously showed that JQ1 prevents several hallmarks of heart failure, including cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction, in a mouse model of aortic con-striction-induced left ventricular pressure overload 30–32 .”
BackgroundSelf-citationPadmanabhan, A., Alexanian, M., Linares-Saldana, R., González-Terán, B., Andreoletti, G., Huang, Y., Connolly, A. J., Kim, W., Hsu, A., Duan, Q., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.047753 · Cited by 60
Self-citationMechanisms of Cardiomyocyte Proliferation and Differentiation in Development and Regeneration
Yester, J., & Kühn, B. (2017) · Current Cardiology Reports · doi:10.1007/s11886-017-0826-1 · Cited by 59
Mechanism of histone deacetylases in cardiac hypertrophy and its therapeutic inhibitors
Han, Y., Nie, J., Wang, D. W., & Li, N. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.931475 · Cited by 58
Epigenetic-based therapy: From single- to multi-target approaches
Benedetti, R., Conte, M., Iside, C., & Altucci, L. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.10.016 · Cited by 56
Perry, M. M., Durham, A. L., Austin, P. J., Adcock, I. M., & Chung, K. F. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.612671 · Cited by 54
“We have previously demonstrated that these cyclin inhibitors are crucial for ASM proliferation (7).”
BRD4: a general regulator of transcription elongation
Altendorfer, E., Mochalova, Y., & Mayer, A. (2022) · Transcription · doi:10.1080/21541264.2022.2108302 · Cited by 59
“Consistently, other studies performed in murine heart tissue, human MOLT4 cells and G1E-ER4 cells revealed an increase in the pausing index upon JQ1 treatment at selected genes and genome-wide suggesting an elongation defect [76,102,103].”
ResultSun, X., Hota, S. K., Zhou, Y.-Q., Novak, S. M., Miguel-Perez, D., Christodoulou, D. C., Seidman, C. E., Seidman, J. G., Gregorio, C. C., Henkelman, R. M., et al. (2017) · Biology Open · doi:10.1242/bio.029512 · Cited by 57
“For example, histone deacetylases (HDACs) and Bromodomain-containing factors play important roles in cardiac gene regulation and remodeling, and have been proposed as potential therapeutic drug targets (Anand et al., 2013; McKinsey, 2012).”
BackgroundConserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity
Shim, W. J., Sinniah, E., Xu, J., Vitrinel, B., Alexanian, M., Andreoletti, G., Shen, S., Sun, Y., Balderson, B., Boix, C. A., et al. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.001 · Cited by 50
BET-ting on chromatin-based therapeutics for heart failure
Haldar, S. M., & McKinsey, T. A. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.05.002 · Cited by 51
“Factors that regulate this latter step of pause release can have profound effects on cell state [4], some of which have been shown to be critically involved in pathologic cardiac remodeling [21, 22] (see section 5 below).”
BackgroundInfluentialSelf-citationEpigenetic regulation in heart failure
Kim, S. Y., Morales, C. R., Gillette, T. G., & Hill, J. A. (2016) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000276 · Cited by 49
Milstone, D. S., Ilyama, M., Chen, M., O’Donnell, P., DAVIS, V. M., Plutzky, J., Brown, J. D., Haldar, S. M., Siu, A., Lau, A. C., et al. (2015) · Circulation Research · doi:10.1161/circresaha.117.306666 · Cited by 49
Self-citationFibrosis in Pathology of Heart and Kidney: From Deep RNA-Sequencing to Novel Molecular Targets
Schreibing, F., Anslinger, T. M., & Kramann, R. (2023) · Circulation Research · doi:10.1161/circresaha.122.321761 · Cited by 51
Xing, J., Lu, W., Liu, R., Wang, Y., Xie, Y., Zhang, H., Shi, Z., Jiang, H., Liu, J. Y.-C., Chen, K., et al. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00098 · Cited by 50
(+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling
Wang, H., Huang, W., Liang, M., Shi, Y., Zhang, C., Li, Q., Liu, M., Shou, Y., Yin, H., Zhu, X., et al. (2018) · Cell & Bioscience · doi:10.1186/s13578-018-0258-7 · Cited by 49
Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration
Ko, S., Choi, T., Russell, J. O., So, J., Monga, S. P., & Shin, D. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.10.017 · Cited by 47
“As Brd4 knockdown results in the same defects elicited by BET inhibition in multiple cancer cells [17,42,43] and the effects of JQ1 on cardiomyocyte hypertrophy appear to be mediated by altering BRD4-dependent transcriptional program [44], Brd4 might be a key BET protein that regulates BEC-driven liver regeneration.”
BackgroundGuetzoyan, L. J., Ingham, R. J., Nikbin, N., Rossignol, J., Wolling, M., Baumert, M., Burgess-Brown, N., Strain-Damerell, C. M., Shrestha, L., Brennan, P. E., et al. (2014) · MedChemComm · doi:10.1039/c4md00007b · Cited by 48
Zhao, Y., Bai, L., Liu, L., McEachern, D., Stuckey, J. A., Meagher, J. L., Yang, C., Xu, R., Zhou, B. N., Hu, Y., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00193 · Cited by 48
Lee, D. U., Katavolos, P., Palanisamy, G. S., Katewa, A., Sioson, C., Corpuz, J., Pang, J., DeMent, K., Choo, E. F., Ghilardi, N., et al. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.03.013 · Cited by 47
Rusconi, F., Ceriotti, P., Miragoli, M., Carullo, P., Salvarani, N., Rocchetti, M., Pasquale, E. D., Rossi, S., Tessari, M. M., Caprari, S., et al. (2016) · Circulation · doi:10.1161/circulationaha.116.021347 · Cited by 50
Li, J., Ma, J., Meng, G., Lin, H., Wu, S. L. Y., Wang, J., Luo, J., Xu, X., Tough, D. F., Lindon, M. J., et al. (2016) · Stem Cell Research · doi:10.1016/j.scr.2016.07.006 · Cited by 47
Olp, M. D., Sprague, D. J., Goetz, C. J., Kathman, S. G., Wynia‐Smith, S. L., Shishodia, S., Summers, S. B., Xu, Z., Statsyuk, A. V., & Smith, B. C. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00058 · Cited by 47
Patrick, J. L., & Reschly, D. J. (1982) · PubMed · Cited by 47
Recent progress and structural analyses of domain‐selective BET inhibitors
Divakaran, A., Harki, D. A., & Pomerantz, W. C. K. (2023) · Medicinal Research Reviews · doi:10.1002/med.21942 · Cited by 48
Hu, X., Lü, X., Liu, R., Ai, N., Cao, Z., Li, Y., Liu, J., Yu, B., Liu, K., Wang, H., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.570812 · Cited by 46
“Consistent with its role in P-TEFb recruitment, BRD4 was shown to be crucial for cell cycle progression (21–23), HIV-1 transcription (15, 16, 34, 35), inflammatory response (33, 36, 37), and cardiac hypertrophy (38, 39).”
BackgroundConserved DNA sequence features underlie pervasive RNA polymerase pausing
Gajos, M., Jasnovidova, O., van Bömmel, A., Freier, S., Vingron, M., & Mayer, A. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab208 · Cited by 50
“Given the recent implications of a change in promoter-proximal pausing and transcription elongation in human pathology (13,66,99,100), an interesting future direction will be to explore potential contributory roles from altered gene-body pausing patterns.”
Luna-Peláez, N., March‐Díaz, R., Ceballos-Chávez, M., Guerrero-Martinez, J. A., Grazioli, P., García‐Gutiérrez, P., Vaccari, T., Massa, V., Reyes, J. C., & García‐Domínguez, M. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1792-x · Cited by 44
Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription
Beagrie, R. A., & Pombo, A. (2016) · BioEssays · doi:10.1002/bies.201600032 · Cited by 44
BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen
Ayoub, A. M., Hawk, L. M. L., Herzig, R. J., Jiang, J., Wisniewski, A. J., Gee, C. T., Zhao, P., Zhu, J.-Y., Berndt, N., Offei-Addo, N. K., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01336 · Cited by 44
“Assays were performed by Reaction Biology using an acetylated Histone4 (1-21), against Brd4(1) with a constant DMSO concentration of 1% (v/v).”
MethodSelf-citationA Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes
Cui, H., Divakaran, A., Hoell, Z. J., Ellingson, M. O., Scholtz, C. R., Zahid, H., Johnson, J. A., Griffith, E. C., Gee, C. T., Lee, A. L., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01779 · Cited by 45
Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface
Wei, J., Joshi, S., Speransky, S. R., Crowley, C., Jayathilaka, N., Lei, X., Wu, Y., Gai, D., Jain, S. K., Hoosien, M., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91068 · Cited by 44
“The BET inhibitor JQ-1 has recently been shown to inhibit pressure overload hypertrophy (58, 59), suggesting that BET proteins act as hypertrophy mediators downstream of the MEF2 acetylation signal.”
BackgroundFoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth
Ferdous, A., Wang, Z. V., Luo, Y., Li, D. ‘., Luo, X., Schiattarella, G. G., Altamirano, F. J., May, H. I., Battiprolu, P. K., Nguyen, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16345-y · Cited by 46
Epigenetic Therapies for Heart Failure: Current Insights and Future Potential
Claudio Napoli, A., Bontempo, P., Palmieri, V., Coscioni, E., Maiello, C., Donatelli, F., & Benincasa, G. (2021) · Vascular Health and Risk Management · doi:10.2147/vhrm.s287082 · Cited by 42
BET inhibitors in cancer therapeutics: a patent review
Ghoshal, A., Yugandhar, D., & Srivastava, A. K. (2016) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2016.1159299 · Cited by 42
BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy
Antolic, A., Wakimoto, H., Jiao, Z., Gorham, J. M., DePalma, S. R., Lemieux, M. E., Conner, D. A., Lee, D. Y., Qi, J., Seidman, J. G., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.138687 · Cited by 41
Self-citationRoles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis
Shao, J., Liu, J., & Zuo, S. (2022) · Cells · doi:10.3390/cells11152347 · Cited by 41
Roles and post‐translational regulation of cardiac class IIa histone deacetylase isoforms
Weeks, K. L., & Avkiran, M. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.282442 · Cited by 40
“…as well as the interplay between HDACs and other epigenetic regulators, such as bromodomain and extra-terminal acetyl-lysine reader proteins (Anand et al. 2013; Spiltoir et al. 2013), is likely to aid the development of new targeted therapies for the prevention or reversal of pathological…”
BackgroundRVX 208: A novel BET protein inhibitor, role as an inducer of apo A‐I/ HDL and beyond
Ghosh, G. C., Bhadra, R., Ghosh, R. K., Banerjee, K., & Gupta, A. (2017) · Cardiovascular Therapeutics · doi:10.1111/1755-5922.12265 · Cited by 42
“BET proteins also act as pause release factor and they are critical for the expression of genes that are central to heart failure pathogenesis.(44) An animal study showed that inhibition of BET proteins decreased myocardial damage related to acute myocardial infarction and this effect was partially mediated by the inh…”
BackgroundThe therapeutic potential of BRD4 in cardiovascular disease
Lin, S., & Du, L. (2020) · Hypertension Research · doi:10.1038/s41440-020-0459-4 · Cited by 40
Genomic enhancers in cardiac development and disease
Anene-Nzelu, C. G., Lee, C. J. M., Tan, W. L. W., Dashi, A., & Foo, R. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00597-2 · Cited by 39
Sengupta, S., Biarnes, M. C., Clarke, R. C., & Jordan, V. C. (2015) · Breast Cancer Research and Treatment · doi:10.1007/s10549-015-3319-1 · Cited by 39
Enhancer-associated RNAs as therapeutic targets
Léveillé, N., Melo, C. A., & Agami, R. (2015) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2015.1029452 · Cited by 38
“Interestingly, genome-wide analysis of Brd4 chromatin occupancy by chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed its association with active promoters and enhancers [31,64].”
BackgroundEpigenetic Mechanisms in Heart Failure Pathogenesis
Salvo, T. G. D., & Haldar, S. M. (2014) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001193 · Cited by 38
“on stress-activated gene induction in the heart via regulation of P-TEFb and transcriptional elongation (Figure 2).(46,111)”
Self-citationDiscovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis
He, Z., Jiao, H., An, Q., Zhang, X., Dan, Z., Xu, J., Liu, H., Ma, L., & Zhao, W. H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.07.018 · Cited by 42
Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases
Guajardo-Correa, E., Silva-Agüero, J. F., Calle, X., Chiong, M., Henríquez, M., García‐Rivas, G., Latorre, M., & Parra, V. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.968373 · Cited by 41
“Moreover, siRNA knockdown of BRD4 in neonatal cardiomyocytes inhibited the hypertrophic response triggered by phenylephrine and diminished the expression of fetal gene program markers (ANP and BNP) associated with CH (Anand et al., 2013).”
BackgroundEpigenetics in cardiac development, function, and disease
Nührenberg, T. G., Gilsbach, R., Preißl, S., Schnick, T., & Hein, L. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1887-8 · Cited by 39
Hoes, M. F., Bömer, N., & van der Meer, P. (2018) · Stem Cells Translational Medicine · doi:10.1002/sctm.18-0052 · Cited by 43
The Role of Bromodomain and Extraterminal Motif (BET) Proteins in Chromatin StructurePreprint
Hsu, S. C., & Blobel, G. A. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.033829 · Cited by 38
“…that targeting BET proteins has therapeutic potential in a wide variety of disorders including cancer (Filippakopoulos et al. 2010; Dawson et al. 2011; Delmore et al. 2011; Zuber et al. 2011; Shi and Vakoc 2014), heart failure (Anand et al. 2013), and inflammatory conditions (Nicodeme et al. 2011).”
BackgroundDiscovery of BET bromodomain inhibitors and their role in target validation
Müller, S., & Knapp, S. (2013) · MedChemComm · doi:10.1039/c3md00291h · Cited by 37
Sun, Y., Xie, Y., Du, L., Sun, J., & Liu, Z. (2018) · Cardiovascular Therapeutics · doi:10.1111/1755-5922.12320 · Cited by 38
Somsen, B. A., Cossar, P. J., Arkin, M. R., Brunsveld, L., & Ottmann, C. (2024) · ChemBioChem · doi:10.1002/cbic.202400214 · Cited by 36
Insights from pharmacological similarity of epigenetic targets in epipolypharmacology
Naveja, J. J., & Medina‐Franco, J. L. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.10.006 · Cited by 33
Super-enhancer lncs to cardiovascular development and disease
Ounzain, S., & Pedrazzini, T. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.11.026 · Cited by 35
Yu, L., Wang, Z., Zhang, Z., Ren, X., Lu, X., & Ding, K. (2015) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666150302110135 · Cited by 34
Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery
Lee, W. H. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002164 · Cited by 33
“Within half a year, these compounds were used by the community to link bromodomains to septic shock [30], leukaemia [32,33], multiple myeloma [34], cardiac hypertrophy [35,36], HIV infection [34,37,38], and MYC regulation [34,38].”
BackgroundProtein–Protein Interaction Modulators for Epigenetic Therapies
(2018) · Advances in Protein Chemistry and Structural Biology · doi:10.1016/bs.apcsb.2017.06.002 · Cited by 31
Sun, J., Gui, Y., Zhou, S., & Zheng, X. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.11.006 · Cited by 38
“For instance, it was found that JQ1 could suppress pressure overload-induced cardiac hypertrophy in mice, and that siRNA knockdown of BRD4 in cultured neonatal cardiac myocytes could prevent the hypertrophic response triggered by external growth cues [139,140].”
Li, Z., Xiao, S.-H., Yang, Y., Chen, C., Lu, T., Chen, Z., Jiang, H., Chen, S., Luo, C., & Zhou, B. N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01784 · Cited by 32
Ramani, M. K. V., Yang, W., Irani, S., & Zhang, Y. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166912 · Cited by 32
Bromodomain inhibitors regulate the C9ORF72 locus in ALS
Zeier, Z. R., Esanov, R., Belle, K. C., Volmar, C., Johnstone, A. L., Halley, P., DeRosa, B. A., Khoury, N., van Blitterswijk, M., Rademakers, R., et al. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.06.017 · Cited by 33
“Genome-wide BRD4 occupancy has been investigated using chromatin immunoprecipitation followed by DNA sequencing revealing that BRD4 associates with active promoters in a context and cell-type specific manner (Loven et al., 2013; Zhang et al., 2012b; Anand et al., 2013).”
The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation
Zhang, M., Wang, B., Urabe, G., Huang, Y., Plutzky, J., Kent, K. C., & Guo, L. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.05.005 · Cited by 30
Self-citationEpigenetic modifications and emerging therapeutic targets in cardiovascular aging and diseases
Qiu, Y., Xu, Q., Xie, P., He, C., Li, Q., Yao, X., Mao, Y. H., Wu, X., & Zhang, T. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107546 · Cited by 33
GC skew defines distinct RNA polymerase pause sites in CpG island promotersPreprint
Kellner, W. A., Bell, J. S. K., & Vertino, P. M. (2015) · Genome Research · doi:10.1101/gr.189068.114 · Cited by 30
“…Pol II at both the promoters and enhancers of active genes, and inhibition of either suppresses not only elongation of promoter-derived mRNAs but also that of noncoding “eRNAs” arising at distal enhancers (Zhang et al. 2012; Anand et al. 2013; Liu et al. 2013; Loven et al. 2013; Kanno et al. 2014).”
BackgroundInfluentialPiquereau, J., Boët, A., Péchoux, C., Antigny, F., Lambert, M., Gressette, M., Ranchoux, B., Gambaryan, N., Domergue, V., Mumby, S. E., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071527 · Cited by 29
“However, the in vitro comparison of dissimilar BET inhibitors (I-BET, I-BET-151, RVX-208, and PFI-1) demonstrated that at equimolar doses, the inhibition of agonist-induced cardiomyocyte hypertrophy was a class effect of BET inhibitors [23].”
BackgroundMethodWang, Y., Zhang, X., Fu, Y. S., Fu, D., Zhen, D., Xing, A., Chen, Y., Gong, G., & Wei, C. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174472 · Cited by 29
Declerck, K., Szic, K. S. V., Palagani, A., Heyninck, K., Haegeman, G., Morand, C., Milenković, D., & Berghe, W. V. (2015) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666150825141720 · Cited by 29
Clinical applications of epigenetics in cardiovascular disease: the long road ahead
Aslibekyan, S. W., Claas, S. A., & Arnett, D. K. (2014) · Translational research · doi:10.1016/j.trsl.2014.04.004 · Cited by 29
“In addition to its effects on apoA-I, BET inhibition suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo by mediating transcriptional pause release in heart failure, suggesting pleiotropic effects on cardiovascular health.(110) Two clinical trials have now been completed that evalua…”
BackgroundDutzmann, J., Haertlé, M., Daniel, J., Kloss, F. J., Musmann, R.-J., Kalies, K., Knöpp, K., Pilowski, C., Sirisko, M., Sieweke, J., et al. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa121 · Cited by 28
Bromodomains: A novel target for the anticancer therapy
Gokani, S., & Bhatt, L. K. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174523 · Cited by 31
Complications of Diabetes Mellitus
Brownlee, M., Aiello, L. P., Cooper, M. E., Vinik, A. I., Plutzky, J., & Boulton, A. J. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00033-2 · Cited by 29
Self-citationImran, A., Lee, J., Go, A., Choi, G., & Lee, K. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.09.025 · Cited by 29
Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes
Pan, H., Qin, K., Guo, Z., Ma, Y., April, C., Gao, X., Andrews, T. G., Bokov, A. F., Zhang, J., Chen, Y., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.028 · Cited by 27
“Deregulation of transcriptional elongation has been previously implicated in pathologic cardiac hypertrophy (Anand et al., 2013; Espinoza-Derout et al., 2009; Sano et al., 2002).”
BackgroundStratton, M. S., & McKinsey, T. A. (2014) · Biochemistry and Cell Biology · doi:10.1139/bcb-2014-0119 · Cited by 31
“Of the BETs, BRD4 is the most extensively characterized and is the family member that has been shown to specifically interact with the P-TEFb complex.”
BackgroundInfluentialElimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts
Nawa, N., Hirata, K., Kawatani, K., Nambara, T., Omori, S., Banno, K., Kokubu, C., Takeda, J., Nishimura, K., Ohtaka, M., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0219592 · Cited by 26
BRD4: an effective target for organ fibrosis
Wei, Q., Gan, C., Sun, M., Xie, Y., Liu, H., Xue, T., Deng, C., Mo, C., & Ye, T. (2024) · Biomarker Research · doi:10.1186/s40364-024-00641-6 · Cited by 29
Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies
Fratta, E., Montico, B., Rizzo, A., Colizzi, F., Sigalotti, L., & Dolcetti, R. (2016) · Oncotarget · doi:10.18632/oncotarget.10033 · Cited by 26
“Furthermore, BET proteins have been found to associate with a great number of active promoters and to converge upon a significant fraction of active enhancers of key genes, including critical oncogenic targets such as c-MYC [96-98].”
BackgroundEpigenetic therapies in heart failure
Alexanian, M., Padmanabhan, A., McKinsey, T. A., & Haldar, S. M. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.04.012 · Cited by 26
“BET inhibition using either JQ1 or siRNAmediated Brd4 knockdown in isolated neonatal rat ventricular myocytes (NRVM) inhibited hallmark features of agonist-induced hypertrophy and suppressed stress-mediated gene induction, supporting a cell-autonomous role of BRD4 in controlling CM cell state during pathological stimu…”
BackgroundMethodInfluentialSelf-citationBtg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
Masumura, Y., Higo, S., Asano, Y., Kato, H., Yan, Y., Ishino, S., Tsukamoto, O., Kioka, H., Hayashi, T., Shintani, Y., et al. (2016) · Scientific Reports · doi:10.1038/srep28592 · Cited by 26
BET-inhibition by JQ1 alleviates streptozotocin-induced diabetic cardiomyopathy
Guo, M., Wang, H., & Chen, W. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.05.018 · Cited by 26
McKinsey, T. A., Vondriska, T. M., & Wang, Y. (2018) · F1000Research · doi:10.12688/f1000research.15797.1 · Cited by 25
Emerging roles of BET proteins in transcription and co‐transcriptional RNA processing
Eischer, N., Arnold, M., & Mayer, A. (2022) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1734 · Cited by 26
Ling, G., & Xu, C.-E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1150304 · Cited by 25
“Transcriptional paused release in heart failure is mediated by BET bromodomain (36), and BET bromodomain inhibitors can inhibit the development of heart failure by regulating innate inflammatory networks (37).”
BackgroundEskandarpour, M., Alexander, R., Adamson, P., & Calder, V. L. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600735 · Cited by 27
“, BRD2, BRD4) are chromatin readers that are involved in gene regulation and the RNA polymerase II “pause release mechanism” (10).”
BackgroundRole of BET Inhibitors in Triple Negative Breast Cancers
Khandekar, D., & Tiriveedhi, V. (2020) · Cancers · doi:10.3390/cancers12040784 · Cited by 26
“In cardiac studies, BET inhibitors were able to inhibit cardiomyocyte damage and overcome pressure-overload effect in hypertension and congestive heart failure models [99].”
BackgroundPharmacology of heart failure: From basic science to novel therapies
Lother, A., & Hein, L. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.07.004 · Cited by 24
Ho, J. S. Y., Jou, E., Khong, P., Foo, R., & Sia, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212010 · Cited by 23
Shi, X., Wang, Y., Zhang, L., Zhao, W., Dai, X., Yang, Y., & Zhang, X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1021820 · Cited by 25
“Dysregulation of BET family proteins which caused a high acetylation levels promotes transcription of multiple oncogenes and participates in the occurrence and development of inflammation and cancers (Anand et al., 2013; Huang et al., 2017; Otto et al., 2019).”
BackgroundThe polar warhead of a TRIM 24 bromodomain inhibitor rearranges a water‐mediated interaction network
Liu, J., Li, F., Bao, H., Jiang, Y., Zhang, S., Ma, R., Gao, J., Wu, J., & Ruan, K. (2017) · FEBS Journal · doi:10.1111/febs.14041 · Cited by 23
Epigenetics in dilated cardiomyopathy
Yu, J., Zeng, C., & Wang, Y. (2019) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000616 · Cited by 23
How progressive cancer endangers the heart: an intriguing and underestimated problem
Ausoni, S., Calamelli, S., Saccà, S., & Azzarello, G. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09869-8 · Cited by 25
“A selective bromodomain inhibitor, JQ1, suppresses pathological remodeling in experimental cardiac hypertrophy [63] and suppresses the TRAF6/NF-κB signaling in a rat model of acute infarction [64].”
Protein acetylation in cardiac aging
Francois, A., Canella, A., Marcho, L. M., & Stratton, M. S. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.04.007 · Cited by 22
Metadata
- Authors
- Anand, P., Brown, J. D., Lin, C. Y., Qi, J., Zhang, R., Artero, P. C., Alaiti, M. A., Bullard, J., Alazem, K., Margulies, K. B., Cappola, T. P., Lemieux, M., Plutzky, J., Bradner, J. E., & Haldar, S. M.
- Affiliations
- University Hospitals of Cleveland (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- University of Pennsylvania (US)
- Harvard University (US)
- Corresponding author
- Bradner, James E.
- Haldar, Saptarsi M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 154
- Issue
- 3
- Pages
- 569-582
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4090947
- OpenAlex
- W2154924534
- Cited by
- 406
- References
- 63
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 18 · 2023: 25 · 2022: 25 · 2021: 36 · 2020: 49 · 2019: 33 · 2018: 28 · 2017: 29 · 2016: 36 · 2015: 42 · 2014: 30 · 2013: 6
- FWCI
- 17.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Heart, Lung, and Blood Institute (T32HL105338, K08HL105678, K08HL086614, R01HL105993, P01HL048743)
- National Cancer Institute (K08CA128972)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK093821)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- heart failure, BET proteins, chromatin acetylation, histone acetyltransferase, cardiac remodeling, cardiomyocyte hypertrophy, epigenetic reader protein, BET inhibition, gene expression regulation, chemical genetics
- MeSH terms
- Animals, Chromatin, Disease Models, Animal, Heart, Cardiomegaly, Heart Failure, Humans, Mice, Inbred C57BL, Transcription Factors, Transcription, Genetic, Protein Structure, Tertiary, Myocytes, Cardiac, Epigenesis, Genetic, Mice, Rats, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
