Kidney tissue homeostasis: role of epitranscriptome in podocyte biology
The incidence of chronic kidney disease is increasing and poses a significant risk by
itself as well as a complication with other lifestyle disorders. And hence, understanding the
cellular and molecular regulation of the kidney is critical.
Nephrogenesis, the process of kidney development occurs mostly during the embryonic stages and is completed soon after birth through a series of mesenchymal to epithelial transition (MET). This process is brought about by an interplay of the signalling pathways, patterning and transcriptional networks orchestrated by transcription factors such as WT1, Pax2 and Six2. However, regulation of gene expression occurs at the transcriptional level as well as the post transcriptional level and there is very little information about the latter.
We have recently shown that the Wilms’ tumour suppressor protein (WT1) is an RNA binding protein (RBP) as well as a transcription factor. WT1 interacts with different subtypes of RNA and thus, plays an important role in RNA stability and microRNA processing in the kidney mesenchyme, and nucleates an RNA network, impinging on signalling pathways critical for development and disease.
Regulatory cascades in kidney development:An unbiased proteomic interaction study was performed to identify RNA binding proteins that are enriched in the nephrogenic system and also interact with the developmental regulator of kidney, WT1. The proteomic investigation study showed that WT1 was part of RNA binding complexes spanning the entire mRNA processing network. The exact contribution of each of these RNA nucleo protein complexes in nephrogenesis will be identified through in vitro and in vivo assays, reporter analysis and physiological investigations.
During the course of identifying the different RNA nucleo-protein (RNP) complexes in nephrogenesis, the m6A modifying methylation complex component, WT1 Associated Protein (WTAP), was found to be associated with some of these RNP complexes. Although, the RNA modifications (also referred to as the epitranscriptome) were identified decades ago, its only very recently been attributed with such diverse regulatory roles. We would like to understand how the RNA regulatory networks, especially, m6A modification regulates different functional outcomes in nephrogenesis.