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  1. Article ; Online: Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases.

    Kulikowski, Ewelina / Rakai, Brooke D / Wong, Norman C W

    Medicinal research reviews

    2020  Volume 41, Issue 1, Page(s) 223–245

    Abstract: Clinical development of bromodomain and extra-terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel ... ...

    Abstract Clinical development of bromodomain and extra-terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic "readers," which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan-BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.
    MeSH term(s) Cell Cycle Proteins ; Humans ; Neoplasms/drug therapy ; Nuclear Proteins ; Protein Domains ; Transcription Factors
    Chemical Substances BRD4 protein, human ; Cell Cycle Proteins ; Nuclear Proteins ; Transcription Factors
    Language English
    Publishing date 2020-09-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 603210-2
    ISSN 1098-1128 ; 0198-6325
    ISSN (online) 1098-1128
    ISSN 0198-6325
    DOI 10.1002/med.21730
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    Zs.A 1764: Show issues Location:
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  2. Article ; Online: Insulin mimetic effect of D-allulose on apolipoprotein A-I gene.

    Haas, Michael J / Parekh, Shrina / Kalidas, Poonam / Richter, Angela / Warda, Firas / Wong, Norman C W / Tokuda, Masaaki / Mooradian, Arshag D

    Journal of food biochemistry

    2022  Volume 46, Issue 2, Page(s) e14064

    Abstract: Several nutrients modulate the transcriptional activity of the apolipoprotein A-I (apo A-I) gene. To determine the influence of rare sugars on apo A-I expression in hepatic (HepG2) and intestinal derived (Caco-2) cell lines, apo A-I, albumin, and SP1 ... ...

    Abstract Several nutrients modulate the transcriptional activity of the apolipoprotein A-I (apo A-I) gene. To determine the influence of rare sugars on apo A-I expression in hepatic (HepG2) and intestinal derived (Caco-2) cell lines, apo A-I, albumin, and SP1 were quantified with enzyme immunoassay and Western blots while mRNA levels were quantified with real-time polymerase chain reaction. The promoter activity was measured using transient transfection assays with plasmids containing various segments and mutations in the promoter. D-allulose and D-tagatose, increased apo A-I concentration in culture media while D-sorbose and D-allose did not have any measurable effects. D-allulose did not increase apo A-I levels in Caco-2 cells. These changes paralleled the increased mRNA levels and promoter activity. D-allulose-response was mapped at the insulin response core element (IRCE). Mutation of the IRCE decreased the ability of D-allulose and insulin to activate the promoter. Treatment of HepG2 cells, but not Caco-2 cells, with D-alluose and insulin increased SP1 expression relative to control cells. D-allulose augmented the expression and IRCE binding of SP1, an essential transcription factor for the insulin on apo A-I promoter activity. D-allulose can modulate some insulin-responsive genes and may have anti-atherogenic properties, in part due to increasing apo A-I production. PRACTICAL APPLICATIONS: Coronary artery disease (CAD) is the number one cause of mortality in industrialized countries. A risk factor associated with CAD is low high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) concentrations in plasma. Thus, novel therapeutic agents or nutrients that upregulate apo A-I production should be identified. D-allulose and D-tagatose are used as sweeteners and may have favorable effects on insulin resistance and diabetes. This study shows that D-allulose and D-tagatose increases apo A-I production through increased transcription factor SP1-binding to insulin response element of the promoter. These sweeteners modulate some insulin responsive genes, increase the production of apo-A-I, and therefore may have anti-atherogenic properties.
    MeSH term(s) Apolipoprotein A-I/genetics ; Caco-2 Cells ; Fructose/pharmacology ; Hep G2 Cells ; Hexoses ; Humans ; Insulin
    Chemical Substances Apolipoprotein A-I ; Hexoses ; Insulin ; psicose (23140-52-5) ; Fructose (30237-26-4) ; tagatose (T7A20Y888Y)
    Language English
    Publishing date 2022-01-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 433846-7
    ISSN 1745-4514 ; 0145-8884
    ISSN (online) 1745-4514
    ISSN 0145-8884
    DOI 10.1111/jfbc.14064
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  3. Article: Insulin mimetic effect of D‐allulose on apolipoprotein A‐I gene

    Haas, Michael J. / Parekh, Shrina / Kalidas, Poonam / Richter, Angela / Warda, Firas / Wong, Norman C. W. / Tokuda, Masaaki / Mooradian, Arshag D.

    Journal of food biochemistry. 2022 Feb., v. 46, no. 2

    2022  

    Abstract: Several nutrients modulate the transcriptional activity of the apolipoprotein A‐I (apo A‐I) gene. To determine the influence of rare sugars on apo A‐I expression in hepatic (HepG2) and intestinal derived (Caco‐2) cell lines, apo A‐I, albumin, and SP1 ... ...

    Abstract Several nutrients modulate the transcriptional activity of the apolipoprotein A‐I (apo A‐I) gene. To determine the influence of rare sugars on apo A‐I expression in hepatic (HepG2) and intestinal derived (Caco‐2) cell lines, apo A‐I, albumin, and SP1 were quantified with enzyme immunoassay and Western blots while mRNA levels were quantified with real‐time polymerase chain reaction. The promoter activity was measured using transient transfection assays with plasmids containing various segments and mutations in the promoter. D‐allulose and D‐tagatose, increased apo A‐I concentration in culture media while D‐sorbose and D‐allose did not have any measurable effects. D‐allulose did not increase apo A‐I levels in Caco‐2 cells. These changes paralleled the increased mRNA levels and promoter activity. D‐allulose‐response was mapped at the insulin response core element (IRCE). Mutation of the IRCE decreased the ability of D‐allulose and insulin to activate the promoter. Treatment of HepG2 cells, but not Caco‐2 cells, with D‐alluose and insulin increased SP1 expression relative to control cells. D‐allulose augmented the expression and IRCE binding of SP1, an essential transcription factor for the insulin on apo A‐I promoter activity. D‐allulose can modulate some insulin‐responsive genes and may have anti‐atherogenic properties, in part due to increasing apo A‐I production. PRACTICAL APPLICATIONS: Coronary artery disease (CAD) is the number one cause of mortality in industrialized countries. A risk factor associated with CAD is low high‐density lipoprotein (HDL) cholesterol and apolipoprotein A‐I (apo A‐I) concentrations in plasma. Thus, novel therapeutic agents or nutrients that upregulate apo A‐I production should be identified. D‐allulose and D‐tagatose are used as sweeteners and may have favorable effects on insulin resistance and diabetes. This study shows that D‐allulose and D‐tagatose increases apo A‐I production through increased transcription factor SP1‐binding to insulin response element of the promoter. These sweeteners modulate some insulin responsive genes, increase the production of apo‐A‐I, and therefore may have anti‐atherogenic properties.
    Keywords albumins ; allose ; apolipoprotein A-I ; coronary artery disease ; diabetes ; enzyme immunoassays ; genes ; industrialization ; insulin ; insulin resistance ; intestines ; mortality ; mutation ; plasmids ; psicose ; quantitative polymerase chain reaction ; risk factors ; sorbose ; tagatose ; therapeutics ; transcription (genetics) ; transcription factors ; transfection
    Language English
    Dates of publication 2022-02
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note JOURNAL ARTICLE
    ZDB-ID 433846-7
    ISSN 1745-4514 ; 0145-8884
    ISSN (online) 1745-4514
    ISSN 0145-8884
    DOI 10.1111/jfbc.14064
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  4. Article ; Online: Dual mechanism: Epigenetic inhibitor apabetalone reduces SARS-CoV-2 Delta and Omicron variant spike binding and attenuates SARS-CoV-2 RNA induced inflammation.

    Fu, Li / Gilham, Dean / Stotz, Stephanie C / Sarsons, Christopher D / Rakai, Brooke D / Tsujikawa, Laura M / Wasiak, Sylwia / Johansson, Jan O / Sweeney, Michael / Wong, Norman C W / Kulikowski, Ewelina

    International immunopharmacology

    2023  Volume 117, Page(s) 109929

    Abstract: The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and ...

    Abstract The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger interferon-I (IFN-I) mediated inflammatory responses for viral clearance and resolution of infection. However, overreactive host IFN-I responses and pro-inflammatory signals drive COVID-19 pathophysiology and disease severity during acute infection. These immune abnormalities also lead to the development of post-COVID syndrome if persistent. Novel therapeutics are urgently required to reduce short- and long-term pathologic consequences associated with SARS-CoV-2 infection. Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, is a candidate for COVID-19 treatment via a dual mechanism of action. In vitro, apabetalone downregulates ACE2 gene expression to limit SARS-CoV-2 entry and propagation. In pre-clinical models and patients treated for cardiovascular disease, apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm (CS) stimulated by various cytokines. Here we show apabetalone treatment of human lung epithelial cells reduces binding of viral spike protein regardless of mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, we demonstrate that apabetalone counters expression of pro-inflammatory factors with roles in CS and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA. Our results support clinical evaluation of apabetalone to treat COVID-19 and post-COVID syndrome regardless of the SARS-CoV-2 variant.
    MeSH term(s) Humans ; SARS-CoV-2 ; RNA, Viral ; COVID-19 ; Angiotensin-Converting Enzyme 2/genetics ; COVID-19 Drug Treatment ; Spike Glycoprotein, Coronavirus/genetics ; Inflammation/drug therapy ; Interferons ; Antibodies ; Cytokine Release Syndrome/drug therapy ; Epigenesis, Genetic
    Chemical Substances RNA, Viral ; apabetalone (8R4A7GDZ1D) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus ; Interferons (9008-11-1) ; Antibodies ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2023-02-23
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2043785-7
    ISSN 1878-1705 ; 1567-5769
    ISSN (online) 1878-1705
    ISSN 1567-5769
    DOI 10.1016/j.intimp.2023.109929
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    Zs.A 5408: Show issues Location:
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  5. Article ; Online: European Society of Cardiology--2009 annual congress. 31 August - 2 September 2009, Barcelona, Spain.

    Wong, Norman C W

    IDrugs : the investigational drugs journal

    2009  Volume 12, Issue 11, Page(s) 675–678

    Abstract: The European Society of Cardiology Annual Congress, held in Barcelona, included topics covering new therapeutic developments in the field of cardiovascular disease. This conference report highlights selected presentations on the development and ... ...

    Abstract The European Society of Cardiology Annual Congress, held in Barcelona, included topics covering new therapeutic developments in the field of cardiovascular disease. This conference report highlights selected presentations on the development and progression of atherosclerosis, imaging techniques for treating atherosclerosis and clinical trials of treatments for cardiovascular disease. Investigational drugs discussed include ticagrelor (AstraZeneca AG).
    MeSH term(s) Animals ; Atherosclerosis/drug therapy ; Atherosclerosis/physiopathology ; Cardiovascular Agents/pharmacology ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/physiopathology ; Clinical Trials as Topic ; Disease Progression ; Drug Delivery Systems ; Drug Design ; Drugs, Investigational/pharmacology ; Humans
    Chemical Substances Cardiovascular Agents ; Drugs, Investigational
    Language English
    Publishing date 2009-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 2086568-5
    ISSN 2040-3410 ; 1369-7056
    ISSN (online) 2040-3410
    ISSN 1369-7056
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    Zs.A 6320: Show issues Location:
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  6. Article ; Online: Coronary Artery Disease - Eighth International Congress. From prevention to intervention.

    Wong, Norman C W

    IDrugs : the investigational drugs journal

    2009  Volume 12, Issue 12, Page(s) 742–746

    Abstract: The International Congress on Coronary Artery Disease, held in Prague, included topics covering new developments in the field of therapeutics for cardiovascular diseases. This conference report highlights selected presentations on clinical and basic ... ...

    Abstract The International Congress on Coronary Artery Disease, held in Prague, included topics covering new developments in the field of therapeutics for cardiovascular diseases. This conference report highlights selected presentations on clinical and basic research, including the future of interventional cardiology, treatments to accompany percutaneous coronary intervention, vascular closure devices, the use of heparin and clopidogrel, applying differential matrix metalloprotease profiling and microRNAs to identify patients for treatment, targeting cathepsins in atherosclerosis, and targeting cholesterol in cardiovascular disease. Investigational drugs discussed include FX-06 (Ikaria Holdings Inc) and RVX-208 (Resverlogix Corp).
    MeSH term(s) Angioplasty, Balloon, Coronary/methods ; Animals ; Cardiovascular Agents/pharmacology ; Cardiovascular Agents/therapeutic use ; Cardiovascular Diseases/physiopathology ; Cardiovascular Diseases/prevention & control ; Cardiovascular Diseases/therapy ; Coronary Artery Disease/physiopathology ; Coronary Artery Disease/prevention & control ; Coronary Artery Disease/therapy ; Drug Design ; Drugs, Investigational/pharmacology ; Drugs, Investigational/therapeutic use ; Humans
    Chemical Substances Cardiovascular Agents ; Drugs, Investigational
    Language English
    Publishing date 2009-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 2086568-5
    ISSN 2040-3410 ; 1369-7056
    ISSN (online) 2040-3410
    ISSN 1369-7056
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  7. Article: The BET inhibitor apabetalone decreases neuroendothelial proinflammatory activation

    Wasiak, Sylwia / Fu, Li / Daze, Emily / Gilham, Dean / Rakai, Brooke D / Stotz, Stephanie C / Tsujikawa, Laura M / Sarsons, Chris D / Studer, Deborah / Rinker, Kristina D / Jahagirdar, Ravi / Wong, Norman C W / Sweeney, Michael / Johansson, Jan O / Kulikowski, Ewelina

    Translational neuroscience

    2023  Volume 14, Issue 1, Page(s) 20220332

    Abstract: Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. ... ...

    Abstract Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of
    Language English
    Publishing date 2023-12-31
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2581219-1
    ISSN 2081-6936 ; 2081-3856
    ISSN (online) 2081-6936
    ISSN 2081-3856
    DOI 10.1515/tnsci-2022-0332
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  8. Article ; Online: Reduction in the risk of major adverse cardiovascular events with the BET protein inhibitor apabetalone in patients with recent acute coronary syndrome, type 2 diabetes, and moderate to high likelihood of non-alcoholic fatty liver disease.

    Toth, Peter P / Schwartz, Gregory G / Nicholls, Stephen J / Khan, Aziz / Szarek, Michael / Ginsberg, Henry N / Johansson, Jan O / Kalantar-Zadeh, Kamyar / Kulikowski, Ewelina / Lebioda, Ken / Wong, Norman C W / Sweeney, Michael / Ray, Kausik K

    American journal of preventive cardiology

    2022  Volume 11, Page(s) 100372

    Abstract: Background: Nonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non- ... ...

    Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression.
    Methods: The Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this
    Results: In 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS
    Conclusions: Amongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.
    Language English
    Publishing date 2022-08-08
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2666-6677
    ISSN (online) 2666-6677
    DOI 10.1016/j.ajpc.2022.100372
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  9. Article ; Online: Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy.

    Fu, Li / Wasiak, Sylwia / Tsujikawa, Laura M / Rakai, Brooke D / Stotz, Stephanie C / Wong, Norman C W / Johansson, Jan O / Sweeney, Michael / Mohan, Connie M / Khan, Aneal / Kulikowski, Ewelina

    Pharmacology research & perspectives

    2022  Volume 10, Issue 3, Page(s) e00949

    Abstract: Fabry disease (FD) is a rare X-linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α-galactosidase. Gb3 deposits activate immune-mediated systemic inflammation, ... ...

    Abstract Fabry disease (FD) is a rare X-linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α-galactosidase. Gb3 deposits activate immune-mediated systemic inflammation, ultimately leading to life-threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP-1 and TNF-α cytokine levels were almost doubled in plasma from ERT-treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2-year period of continuous ERT. Apabetalone is a clinical-stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2-selective BETi, dose dependently reduced the production of MCP-1 and IL-12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2-selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2-selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials.
    MeSH term(s) Cytokines/metabolism ; Enzyme Replacement Therapy ; Epigenesis, Genetic ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; Fabry Disease/metabolism ; Humans ; Immunity, Innate ; Inflammation/drug therapy ; Inflammation/genetics ; Leukocytes, Mononuclear/metabolism ; Quinazolinones
    Chemical Substances Cytokines ; Quinazolinones ; apabetalone (8R4A7GDZ1D)
    Language English
    Publishing date 2022-04-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2740389-0
    ISSN 2052-1707 ; 2052-1707
    ISSN (online) 2052-1707
    ISSN 2052-1707
    DOI 10.1002/prp2.949
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  10. Article ; Online: Breaking boundaries: Pan BETi disrupt 3D chromatin structure, BD2-selective BETi are strictly epigenetic transcriptional regulators.

    Tsujikawa, Laura M / Kharenko, Olesya A / Stotz, Stephanie C / Rakai, Brooke D / Sarsons, Christopher D / Gilham, Dean / Wasiak, Sylwia / Fu, Li / Sweeney, Michael / Johansson, Jan O / Wong, Norman C W / Kulikowski, Ewelina

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2022  Volume 152, Page(s) 113230

    Abstract: Background: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically ... ...

    Abstract Background: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability.
    Methods: Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNFα was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays.
    Findings: We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription.
    Interpretation: BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.
    MeSH term(s) COVID-19 ; Cell Cycle Proteins/metabolism ; Chromatin ; Endothelial Cells/metabolism ; Epigenesis, Genetic ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism
    Chemical Substances BRD4 protein, human ; Cell Cycle Proteins ; Chromatin ; Nuclear Proteins ; Transcription Factors
    Language English
    Publishing date 2022-06-07
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2022.113230
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