Limits...
The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs.

Schlesinger J, Schueler M, Grunert M, Fischer JJ, Zhang Q, Krueger T, Lange M, Tönjes M, Dunkel I, Sperling SR - PLoS Genet. (2011)

Bottom Line: Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth.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.

View Article: PubMed Central - PubMed

Affiliation: Group Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

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.

Show MeSH

Related in: MedlinePlus

Srf-centered transcription network integrating Srf binding events, H3ac, miRNAs, and differential expression in Srf knockdown.The shown transcription network is based on an extensive literature search [7], [26], [41], [43], [79]–[120] and integration of our findings. Our data add the regulatory content to the nodes, which are connected by referenced interactions. It illustrates the common regulation by Srf and histone 3 acetylation (H3ac) as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Data based on Illumina expression array, ChIP-chip/seq, miRNA-seq and qPCR. Srf binding and H3ac occurrence are depicted in small boxes and up- (red) or downregulation (green) in Srf knockdown is further indicated.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3040678&req=5

pgen-1001313-g007: Srf-centered transcription network integrating Srf binding events, H3ac, miRNAs, and differential expression in Srf knockdown.The shown transcription network is based on an extensive literature search [7], [26], [41], [43], [79]–[120] and integration of our findings. Our data add the regulatory content to the nodes, which are connected by referenced interactions. It illustrates the common regulation by Srf and histone 3 acetylation (H3ac) as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Data based on Illumina expression array, ChIP-chip/seq, miRNA-seq and qPCR. Srf binding and H3ac occurrence are depicted in small boxes and up- (red) or downregulation (green) in Srf knockdown is further indicated.

Mentions: In addition to a genome-wide perspective, our analysis also provides useful information on the level of individual genes. We conducted an extensive literature search and built an Srf centered cardiac transcription network, where we subsequently integrated our findings from the Srf and histone 3 acetylation ChIP and Srf siRNA-mediated knockdown experiments (Figure 7). Thus our data add regulatory content to the nodes, which are connected by referenced interactions. The network depicts common regulation by Srf and H3ac as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Target genes important in the cardiovascular context are arranged to their biological roles like regulation in muscle contractility or cardiac growth and conduction. As an example the apoptotic machinery is regulated at all three levels (Srf, H3ac and miRNAs) through several pathways involving pro-apoptotic (Casp3, miR-320, Hsp20/a8/a5, Bax) as well as anti-apoptotic (miR-21, Bcl2, Mcl1) genes.


The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs.

Schlesinger J, Schueler M, Grunert M, Fischer JJ, Zhang Q, Krueger T, Lange M, Tönjes M, Dunkel I, Sperling SR - PLoS Genet. (2011)

Srf-centered transcription network integrating Srf binding events, H3ac, miRNAs, and differential expression in Srf knockdown.The shown transcription network is based on an extensive literature search [7], [26], [41], [43], [79]–[120] and integration of our findings. Our data add the regulatory content to the nodes, which are connected by referenced interactions. It illustrates the common regulation by Srf and histone 3 acetylation (H3ac) as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Data based on Illumina expression array, ChIP-chip/seq, miRNA-seq and qPCR. Srf binding and H3ac occurrence are depicted in small boxes and up- (red) or downregulation (green) in Srf knockdown is further indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040678&req=5

pgen-1001313-g007: Srf-centered transcription network integrating Srf binding events, H3ac, miRNAs, and differential expression in Srf knockdown.The shown transcription network is based on an extensive literature search [7], [26], [41], [43], [79]–[120] and integration of our findings. Our data add the regulatory content to the nodes, which are connected by referenced interactions. It illustrates the common regulation by Srf and histone 3 acetylation (H3ac) as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Data based on Illumina expression array, ChIP-chip/seq, miRNA-seq and qPCR. Srf binding and H3ac occurrence are depicted in small boxes and up- (red) or downregulation (green) in Srf knockdown is further indicated.
Mentions: In addition to a genome-wide perspective, our analysis also provides useful information on the level of individual genes. We conducted an extensive literature search and built an Srf centered cardiac transcription network, where we subsequently integrated our findings from the Srf and histone 3 acetylation ChIP and Srf siRNA-mediated knockdown experiments (Figure 7). Thus our data add regulatory content to the nodes, which are connected by referenced interactions. The network depicts common regulation by Srf and H3ac as well as the impact of the posttranscriptional modulation of expression levels by miRNAs. Target genes important in the cardiovascular context are arranged to their biological roles like regulation in muscle contractility or cardiac growth and conduction. As an example the apoptotic machinery is regulated at all three levels (Srf, H3ac and miRNAs) through several pathways involving pro-apoptotic (Casp3, miR-320, Hsp20/a8/a5, Bax) as well as anti-apoptotic (miR-21, Bcl2, Mcl1) genes.

Bottom Line: Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth.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.

View Article: PubMed Central - PubMed

Affiliation: Group Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

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.

Show MeSH
Related in: MedlinePlus