The first holistic molecular multi-level modeling approach to unravel the human transcript tissue-regulome and beyond

• Applicant: Professor Dr. Andreas Gruber
• Subject Area: Bioinformatics and Theoretical Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517370297

The expression level of specific transcript isoforms depends on a multitude of regulators, including epigenetic regulators, transcription factors, splicing regulators, 3’ end processing factors as well as microRNAs and an array of RNA-binding proteins that regulate the stability and localization of transcripts. In human, there exist several thousand such regulators, which makes the deconvolution of isoform expression changes into the individual factors that have shaped specific transcriptional patterns a non-trivial problem. As there exist no experimental methods that are able to measure the activity of all possibly involved regulators in parallel, in recent years a major research challenge was the development of computational methods that enable the identification of transcript isoform expression regulators from genome-scale expression changes. However, even though transcript expression is regulated by a multitude of molecular processes, current modeling approaches typically consider only one specific layer of regulation, such as transcription or splicing, which makes it difficult to integrate the results of the available approaches in order to gain a holistic picture of the molecular processes involved. Within this project we will develop the first unified molecular multi-level modeling framework, termed TIERI-pro, that integrates all major processes of transcript isoform expression regulation. TIERI-pro, standing for Transcript Isoform Expression Regulation Impact-profiler, will make use of standard RNA sequencing (RNA-seq) data to identify the sequence motifs that regulate transcript isoform expression and characterize their position dependency relative to transcription start sites, splice sites, 3’ end processing sites as well as transcript 3’ untranslated regions. Running TIERI-pro on a huge dataset that comprises of 32 tissues we will chart the first comprehensive landscape of regulatory sequence elements that drive tissue-specific transcript isoform expression in human. We will validate our most interesting findings making use of orthogonal datasets. To make TIERI-pro available to the scientific community we will implement a web service that enables to run TIERI-pro in a fully automated manner on any RNA-seq dataset of interest.

• DFG Programme: Research Grants