A Computational Approach for Identification of Potential Regulatory Motifs and Associated TFs Controlling the Expression of UMOD Gene in Kidney

Abstract

Uromodujin is known to be involved in various biological processes like regulation of ion homeostasis, cellular defence response, excretion, calcium. ion binding. Alteration in its protein levels leads to several kidney disorders: ADMCKD2, FJHN, HNFJl, MCKD2, UAKD and AKI. Many in vitro, mouse model studies have been conducted to explore regulation of UMOD however its association with various kidney disorders is still unclear. Our study is focused at transcriptional level to uncover transcription factors (TFs) that bind specifically to the regulatory regions of UMOD gene thus contributing to the identity, physiology & development of kidney. UMOD transcripts were found to be specifically expressed in kidney when their transcript levels were compared using Illumina generated RNA-seq data from the Human Body Map 2.0 Project for 16 different human tissues. Application of phylogenetic foot-printing algorithms by employing the MEME-SUITE of tools allowed the identification of 10 high confidence binding motifs and corresponding positions specific weight matrices in the up stream regulatory binding regions of UMOD orthologs from a diverse set of 8 primates and 7 rodents. We further analyzed the predicted binding motifs by Tom-Tom tool from the suite to identify transcription factors, which have a high tendency, and specificity to bind to these discovered motifs. Our study enabled the identification of a reliable list of transcription factors that could potentially bind to these ten discovered motifs of UMOD, which included TFs such as GATA3, HMF- 1, SPl, SOX5, STAT3, FOXA2, KLF4, and SMAD3 etc. Some of the TFs identified have no functional evidence in human but were annotated in other species. Our study allowed the discovery of regulatory motifs as well as the identification of TFs, which can likely bind to these elements to control the expression of the UMOD gene in kidney cells.