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1.
Nat Commun ; 13(1): 4345, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896549

RESUMO

Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited.


Assuntos
Quinases Ciclina-Dependentes , Insuficiência Cardíaca , Animais , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Camundongos , RNA Polimerase II , Volume Sistólico
2.
J Lit Sci ; 14(1-2): 94-107, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-36545402
3.
JACC Basic Transl Sci ; 4(5): 567-574, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768474

RESUMO

In this study low-input RNA-sequencing was used to annotate the molecular identity of endothelial cells isolated and immunopurified with CD144 microbeads. Using this technique, comparative gene expression profiling from healthy subjects and patients with type 2 diabetes mellitus identified both known and novel pathways linked with EC dysfunction. Modeling of diabetes by treating cultured ECs with high glucose identified shared changes in gene expression in diabetic cells. Overall, the data demonstrate how purified ECs from patients can be used to generate new hypotheses about mechanisms of human vascular disease.

4.
Proc Natl Acad Sci U S A ; 115(9): 2144-2149, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29444854

RESUMO

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.


Assuntos
Adipócitos/fisiologia , Tecido Adiposo/citologia , Regulação da Expressão Gênica/fisiologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Adipogenia , Tecido Adiposo/fisiologia , Animais , Diferenciação Celular , Masculino , Camundongos
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