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.
Highlights
Transcription factors (TFs) regulate the expression of genes and genetic programs to maintain survival and adaption to the environment in adult organisms as well as in embryoand organogenesis
As we have recently suggested in PC-TraFF (Meckbach et al, 2015), we prefer in this study the usage of transcription factor binding sites (TFBSs) pairs instead of composite regulatory modulues (CRMs), since those pairs were detected in a set of sequences
We identified: (i) 63 TFBS pairs based on 429 differentially expressed genes (DEGs) for the mesoderm induction stage; (ii) 82 TFBS pairs based on 1233 DEGs for the early cardiac specification stage; (iii) 24 TFBS pairs based on 36 DEGs for the late cardiac specification stage; (iv) 52 TFBS pairs based on 205 DEGs for the early cardiac maturation stage; (v) 76 TFBS pairs based on 964 DEGs for the late cardiac maturation stage
Summary
Transcription factors (TFs) regulate the expression of genes and genetic programs to maintain survival and adaption to the environment in adult organisms as well as in embryoand organogenesis. In mammalian tissues TFs often work in combinatorial interactions for precise regulation of specific programs (Boyer et al, 2005; Odom et al, 2006; Hu and Gallo, 2010; Neph et al, 2012). Such interactions can be positive, resulting in an enhanced expression of a gene or negative, resulting in reduced expression of a target gene. The identification of co-occurring transcription factor binding sites (TFBSs) in the promoter regions of regulated genes indicate potential combinatorial interactions between TFs that are important for understanding the molecular mechanisms, e.g., of tissue development during embryogenesis. A complete survey of potential TF interactions by co-occurring TFBSs in the promoter regions of genes which regulate cardiac development is still missing, but needed to understand embryonic cardiac development, in particular of cardiomyocytes (CMs)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
