title: Computational Detection of Stage-Specific Transcription Factor Clusters during Heart Development.
abstract: Transcription factors (TFs) regulate gene expression in living organisms. In higher organisms, TFs often interact in non-random combinations with each other to control gene transcription. Understanding the interactions is key to decipher mechanisms underlying tissue development. The aim of this study was to analyze co-occurring transcription factor binding sites (TFBSs) in a time series dataset from a new cell-culture model of human heart muscle development in order to identify common as well as specific co-occurring TFBS pairs in the promoter regions of regulated genes which can be essential to enhance cardiac tissue developmental processes. To this end, we separated available RNAseq dataset into five temporally defined groups: (i) mesoderm induction stage; (ii) early cardiac specification stage; (iii) late cardiac specification stage; (iv) early cardiac maturation stage; (v) late cardiac maturation stage, where each of these stages is characterized by unique differentially expressed genes (DEGs). To identify TFBS pairs for each stage, we applied the MatrixCatch algorithm, which is a successful method to deduce experimentally described TFBS pairs in the promoters of the DEGs. Although DEGs in each stage are distinct, our results show that the TFBS pair networks predicted by MatrixCatch for all stages are quite similar. Thus, we extend the results of MatrixCatch utilizing a Markov clustering algorithm (MCL) to perform network analysis. Using our extended approach, we are able to separate the TFBS pair networks in several clusters to highlight stage-specific co-occurences between TFBSs. Our approach has revealed clusters that are either common (NFAT or HMGIY clusters) or specific (SMAD or AP-1 clusters) for the individual stages. Several of these clusters are likely to play an important role during the cardiomyogenesis. Further, we have shown that the related TFs of TFBSs in the clusters indicate potential synergistic or antagonistic interactions to switch between different stages. Additionally, our results suggest that cardiomyogenesis follows the hourglass model which was already proven for Arabidopsis and some vertebrates. This investigation helps us to get a better understanding of how each stage of cardiomyogenesis is affected by different combination of TFs. Such knowledge may help to understand basic principles of stem cell differentiation into cardiomyocytes.
authors.affiliation: University Medical Center Göttingen, Institute of Bioinformatics, Georg-August-University GöttingenGöttingen, Germany; Heart Research Center Göttingen, University Medical Center Göttingen, Institute of Pharmacology and Toxicology, Georg-August-University GöttingenGöttingen, Germany; DZHK (German Centre for Cardiovascular Research)Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeidler
authors.affiliation: University Medical Center Göttingen, Institute of Bioinformatics, Georg-August-University Göttingen Göttingen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Meckbach
authors.affiliation: University Medical Center Göttingen, Institute of Bioinformatics, Georg-August-University Göttingen Göttingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tacke
authors.affiliation: Heart Research Center Göttingen, University Medical Center Göttingen, Institute of Pharmacology and Toxicology, Georg-August-University GöttingenGöttingen, Germany; DZHK (German Centre for Cardiovascular Research)Göttingen, Germany.
authors.forename: Farah S
authors.initials: FS
authors.lastname: Raad
authors.affiliation: Heart Research Center Göttingen, University Medical Center Göttingen, Institute of Pharmacology and Toxicology, Georg-August-University GöttingenGöttingen, Germany; DZHK (German Centre for Cardiovascular Research)Göttingen, Germany.
authors.forename: Angelica
authors.initials: A
authors.lastname: Roa
authors.affiliation: Institute of Cardiovascular Regeneration, Goethe University FrankfurtFrankfurt, Germany; DZHK (German Centre for Cardiovascular Research)Frankfurt, Germany.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Heart Research Center Göttingen, University Medical Center Göttingen, Institute of Pharmacology and Toxicology, Georg-August-University GöttingenGöttingen, Germany; DZHK (German Centre for Cardiovascular Research)Göttingen, Germany.
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.affiliation: University Medical Center Göttingen, Institute of Bioinformatics, Georg-August-University GöttingenGöttingen, Germany; DZHK (German Centre for Cardiovascular Research)Göttingen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Wingender
authors.affiliation: University Medical Center Göttingen, Institute of Bioinformatics, Georg-August-University Göttingen Göttingen, Germany.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gültas
keywords: Markov clustering; MatrixCatch; cardiomyogenesis; engineered heart muscle; transcription factor collaboration