IGF2BP1 as a novel m6A reader in autosomal dominant polycystic kidney disease

• Applicants: Professor Dr. Markus Landthaler; Professor Dr. Roman-Ulrich Müller
• Subject Area: Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568817395

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder, affecting approximately 1 in 1,000 individuals. It is characterized by progressive cyst development and kidney enlargement, often culminating in kidney failure by mid-to-late adulthood. Despite the relevant disease burden, only one targeted therapy (tolvaptan) is currently available, with limited efficacy, no impact on extrarenal manifestations and relevant side effects. Recent insights into epitranscriptomic regulation, particularly N6-methyladenosine (m⁶A) RNA modifications, have opened promising new avenues in disease biology. Recently published work provided evidence of increased m⁶A methylation as a disease driver in polycystic kidney disease. However, the direct molecular mediator of this RNA-modification towards disease progression remained elusive. Our preliminary studies using enhanced RNA-interactome capture (eRIC) identified significantly increased RNA-association of insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) in kidneys of the Pkd1RC/RC mouse model - a validated genetic model of ADPKD. This protein is not only a known "reader" of m⁶A modifications but also implicated in pro-proliferative signaling in various disease contexts. Building on this compelling observation, our proposal aims to elucidate the role of IGF2BP1 and its interaction with m⁶A-modified transcripts in the progression of ADPKD. Our central hypothesis is that IGF2BP1 serves as a key mediator of m⁶A-driven cystogenesis, acting through stabilization and translation of pro-cystogenic mRNAs. This project is guided by three specific objectives: 1. Define IGF2BP1-target mRNAs in ADPKD by comparing transcript interactions in wild-type and Pkd1-deficient settings. 2. Determine the role of m6A RNA methylation in modulating IGF2BP1 RNA binding, as well as the fate (stability and translation) of its mRNA targets. 3. Examine the in-vivo modulation of m6A RNA methylation by loss of Pkd1 and evaluate the therapeutic potential of modulating m6A methylation using METTL3 inhibitors. To accomplish this, we will integrate direct RNA sequencing (Nanopore technology), mass spectrometry-based m⁶A quantification, and pharmacologic intervention with state-of-the-art m⁶A inhibitors. Our findings will offer a deeper understanding of the interplay between RNA modifications and cystogenic signaling, potentially revealing IGF2BP1 and the m⁶A machinery as novel, targetable nodes in ADPKD. The proposed research is innovative in its mechanistic focus on RNA biology within a disease framework largely unexplored from this angle. It has significant translational potential, especially given the current clinical development of m⁶A-targeted therapies. By teaming up two research groups with highly complementary expertise in RNA biology and kidney disease, our study aims to uncover actionable insights that can redefine therapeutic strategies for ADPKD in the future.

• DFG Programme: Research Grants