Abstract: SA-PO327
The Hippo Effector Tead1 Interacts with Wt1 on a Gene-Regulatory Level by Co-Binding at Podocyte Enhancers
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Rahmatollahi, Mahdieh, University of Cologne, Cologne, Germany
- Padvitski, Tsimafei, University of Cologne, Köln, Germany
- Schermer, Bernhard, University of Cologne, Cologne, Germany
- Benzing, Thomas, University of Cologne, Cologne, Germany
- Beyer, Andreas, University of Cologne, Köln, Germany
- Kann, Martin, University of Cologne, Cologne, Germany
Background
In a genome-wide analysis of gene-regulatory functions of the transcription factor (TF) Wt1 in podocytes we identified an interaction of Wt1 with hippo signaling, which has since emerged as a key pathway relevant to podocyte health and disease. However, gene regulatory effects of hippo signaling in podocytes have not been examined in detail. Here we investigate Wt1 and Tead1 co-regulation in wildtype podocytes in vivo by ChIPseq.
Methods
ChIP-seq for Tead1 and Wt1 was carried out on wildtype mouse glomeruli. Bioinformatic analyses were conducted using standard software and algorithms.
Results
ChIP-seq for Tead1 on mouse glomeruli identified more than 19,000 high confidence and reproducible Tead1 peaks. Tead1 binding occurred at both, promoters and enhancers as indicated by histone modification signatures obtained from ENCODE ChIPseq data. Functional analysis of Tead1 binding events by GO enrichment algorithms revealed differential functions of enhancer vs promoter binding. Promoter binding sites were predominantly located at genes involved in pathways canonically linked to hippo signaling such as regulation of apoptosis and cell cycle. In contrast, enhancer binding occurred at genes of signaling pathways highly relevant to podocytes, such as integrin signaling, the actin cytoskeleton, and Tgf-beta/Smad signaling. Tead1 also bound enhancers relevant to Vegf-, and PDGF-signaling genes suggesting novel links between hippo signaling and further signaling pathways in podocytes as well as novel contexts of hippo signaling in general.
Integrative analysis of Wt1 and Tead1 ChIPseq data showed co-binding of the two TFs in ~7,000 instances with predominance of enhancer binding events. Enhancer co-binding of Wt1 and Tead1 showed speicifc overrepresentation of genes relevant to adherens junctions and focal adhesions when compared to datasets obtained from one TF only. Furthermore, many of the cis-regulatory regions co-bound by Wt1 and Tead1 were associated with genes relevant to glomerular disease and FSGS in particular.
Conclusion
In summary, integrative analysis of Tead1 and Wt1 ChIPseq data in podocytes in vivo reveals novel candidate pathways interacting with hippo signaling. We identify a functional interaction of the TFs to control cell-adhesion signaling bearing high relevance to glomerular disease.