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  The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MircoRNAs

Schlesinger, J., Schueler, M., Grunert, M., Fischer, J. J., Zhang, Q., Krueger, T., et al. (2011). The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MircoRNAs. PLoS Genetics, 7(2): e1001313. doi:10.1371/journal.pgen1001313.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F095-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F096-A
Genre: Journal Article

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© 2011 Schlesinger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 Creators:
Schlesinger, Jenny1, Author              
Schueler, Markus1, Author              
Grunert, Marcel1, Author              
Fischer, Jenny J.1, Author              
Zhang, Qin1, Author
Krueger, Tammo1, Author
Lange, Martin1, Author
Tönjes, Martje1, Author              
Dunkel, Ilona2, Author              
Sperling, Silke1, Author              
Affiliations:
1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433550              
2Computational Epigenetics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479658              

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 Abstract: The transcriptome, as the pool of all transcribed elements in a given cell, is regulated by the interaction between different molecular levels, involving epigenetic, transcriptional, and post-transcriptional mechanisms. However, many previous studies investigated each of these levels individually, and little is known about their interdependency. We present a systems biology study integrating mRNA profiles with DNA–binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf), activating histone modifications (H3ac, H4ac, H3K4me2, and H3K4me3), and microRNA profiles obtained in wild-type and RNAi–mediated knockdown. Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth. We provide insights into the combinatorial regulation by cardiac transcription factors and show that they can partially compensate each other's function. Genes regulated by multiple transcription factors are less likely differentially expressed in RNAi knockdown of one respective factor. In addition to the analysis of the individual transcription factors, we found that histone 3 acetylation correlates with Srf- and Gata4-dependent gene expression and is complementarily reduced in cardiac Srf knockdown. Further, we found that altered microRNA expression in Srf knockdown potentially explains up to 45% of indirect mRNA targets. Considering all three levels of regulation, we present an Srf-centered transcription network providing on a single-gene level insights into the regulatory circuits establishing respective mRNA profiles. In summary, we show the combinatorial contribution of four DNA–binding transcription factors in regulating the cardiac transcriptome and provide evidence that histone modifications and microRNAs modulate their functional consequence. This opens a new perspective to understand heart development and the complexity cardiovascular disorders.

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Language(s): eng - English
 Dates: 2011-02-17
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pgen1001313
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Title: PLoS Genetics
  Other : PLoS Genet.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 7 (2) Sequence Number: e1001313 Start / End Page: - Identifier: ISSN: 1553-7390
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180