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Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling.

Publication ,  Journal Article
Karbassi, E; Rosa-Garrido, M; Chapski, DJ; Wu, Y; Ren, S; Wang, Y; Stefani, E; Vondriska, TM
Published in: J Mol Cell Cardiol
March 2019

Heart failure is associated with hypertrophying of cardiomyocytes and changes in transcriptional activity. Studies from rapidly dividing cells in culture have suggested that transcription may be compartmentalized into factories within the nucleus, but this phenomenon has not been tested in vivo and the role of nuclear architecture in cardiac gene regulation is unknown. While alterations to transcription have been linked to disease, little is known about the regulation of the spatial organization of transcription and its properties in the pathological setting. In the present study, we investigate the structural features of endogenous transcription factories in the heart and determine the principles connecting chromatin structure to transcriptional regulation in vivo. Super-resolution imaging of endogenous RNA polymerase II clusters in neonatal and adult cardiomyocytes revealed distinct properties of transcription factories in response to pathological stress: neonatal nuclei demonstrated changes in number of clusters, with parallel increases in nuclear area, while the adult nuclei underwent changes in size and intensity of RNA polymerase II foci. Fluorescence in situ hybridization-based labeling of genes revealed locus-specific relationships between expression change and anatomical localization-with respect to nuclear periphery and heterochromatin regions, both sites associated with gene silencing-in the nuclei of cardiomyocytes in hearts (but not liver hepatocytes) of mice subjected to pathologic stimuli that induce heart failure. These findings demonstrate a role for chromatin organization and rearrangement of nuclear architecture for cell type-specific transcription in vivo during disease. RNA polymerase II ChIP and chromatin conformation capture studies in the same model system demonstrate formation and reorganization of distinct nuclear compartments regulating gene expression. These findings reveal locus-specific compartmentalization of stress-activated, housekeeping and silenced genes in the anatomical context of the endogenous nucleus, revealing basic principles of global chromatin structure and nuclear architecture in the regulation of gene expression in healthy and diseased conditions.

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Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

March 2019

Volume

128

Start / End Page

198 / 211

Location

England

Related Subject Headings

  • Transcriptional Activation
  • Transcription, Genetic
  • RNA Polymerase II
  • Myocytes, Cardiac
  • Molecular Imaging
  • Mice
  • In Situ Hybridization, Fluorescence
  • Humans
  • Heart Failure
  • Heart
 

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Karbassi, E., Rosa-Garrido, M., Chapski, D. J., Wu, Y., Ren, S., Wang, Y., … Vondriska, T. M. (2019). Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. J Mol Cell Cardiol, 128, 198–211. https://doi.org/10.1016/j.yjmcc.2019.02.003
Karbassi, Elaheh, Manuel Rosa-Garrido, Douglas J. Chapski, Yong Wu, Shuxun Ren, Yibin Wang, Enrico Stefani, and Thomas M. Vondriska. “Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling.J Mol Cell Cardiol 128 (March 2019): 198–211. https://doi.org/10.1016/j.yjmcc.2019.02.003.
Karbassi E, Rosa-Garrido M, Chapski DJ, Wu Y, Ren S, Wang Y, et al. Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. J Mol Cell Cardiol. 2019 Mar;128:198–211.
Karbassi, Elaheh, et al. “Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling.J Mol Cell Cardiol, vol. 128, Mar. 2019, pp. 198–211. Pubmed, doi:10.1016/j.yjmcc.2019.02.003.
Karbassi E, Rosa-Garrido M, Chapski DJ, Wu Y, Ren S, Wang Y, Stefani E, Vondriska TM. Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. J Mol Cell Cardiol. 2019 Mar;128:198–211.
Journal cover image

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

March 2019

Volume

128

Start / End Page

198 / 211

Location

England

Related Subject Headings

  • Transcriptional Activation
  • Transcription, Genetic
  • RNA Polymerase II
  • Myocytes, Cardiac
  • Molecular Imaging
  • Mice
  • In Situ Hybridization, Fluorescence
  • Humans
  • Heart Failure
  • Heart