NDLI: Acute targeting of general transcription factor IIB restricts cardiac hypertrophy via selective inhibition of gene transcription.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sayed, Danish Yang, Zhi He, Minzhen Pfleger, Jessica M. Abdellatif, Maha
Description	Author Affiliation: Sayed D ( From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark. abdellma@njms.rutgers.edu sayeddh@njms.rutgers.edu.); Yang Z ( From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark.); He M ( From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark.); Pfleger JM ( From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark.); Abdellatif M ( From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark. abdellma@njms.rutgers.edu sayeddh@njms.rutgers.edu.)
Abstract	BACKGROUND: We previously reported that specialized and housekeeping genes are differentially regulated via de novo recruitment and pause-release of RNA polymerase II, respectively, during cardiac hypertrophy. However, the significance of this finding remains to be examined. Therefore, the purpose of this study was to determine the mechanisms that differentially regulate these gene groups and exploit them for therapeutic targeting. METHODS AND RESULTS: Here, we show that general transcription factor IIB (TFIIB) and cyclin-dependent kinase 9 are upregulated during hypertrophy, both targeted by microRNA-1, and play preferential roles in regulating those 2 groups of genes. Chromatin immunoprecipitation-sequencing reveals that TFIIB is constitutively bound to all paused, housekeeping, promoters, whereas de novo recruitment of TFIIB and polymerase II is required for specialized genes that are induced during hypertrophy. We exploited this dichotomy to acutely inhibit induction of the latter set, which encompasses cardiomyopathy, immune reaction, and extracellular matrix genes, using locked nucleic acid-modified antisense TFIIB oligonucleotide treatment. This resulted in suppression of all specialized genes, while sparing the housekeeping ones, and, thus, attenuated pathological hypertrophy. CONCLUSIONS: The data for the first time reveal distinct general TFIIB dynamics that regulate specialized versus housekeeping genes during cardiac hypertrophy. Thus, by acutely targeting TFIIB, we were able to inhibit selectively the former set of genes and ameliorate pressure overload hypertrophy. We also demonstrate the feasibility of acutely and reversibly targeting cardiac mRNA for therapeutic purposes using locked nucleic acid-modified antisense oligonucleotides.
File Format	HTM / HTML
ISSN	19413289
e-ISSN	19413297
DOI	10.1161/CIRCHEARTFAILURE.114.001660
Journal	Circulation: Heart Failure
Issue Number	1
Volume Number	8
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2015-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Cardiology Cardiomegaly Genetics Myocytes, Cardiac Metabolism Transcription Factor Tfiib Transcription, Genetic Animals Blotting, Western Pathology Cells, Cultured Disease Models, Animal Immunohistochemistry Mice Mice, Inbred C57bl Promoter Regions, Genetic Rats, Sprague-dawley Reverse Transcriptase Polymerase Chain Reaction Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine

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