Gene regulatory network inference in long-lived C. elegans reveals modular properties that are predictive of novel aging genes

We design a wisdom-of-the-crowds GRN inference pipeline and couple it to complex network analysis to understand the organizational principles governing gene regulation in long-lived glp-1/Notch Caenorhabdities legans. The GRN has three layers (input, core, and output) and is topologically equivalent to bowtie/hourglass structures prevalent among metabolic networks. To assess the functional importance of structural layers, we screened 80% of regulators and discovered 50 new aging genes, 86% with human orthologues. Genes essential for longevity-including ones involved in insulin-like signaling (ILS)-are at the core, indicating that GRN's structure is predictive of functionality. We used in vivo reporters and a novel functional network covering 5,497 genetic interactions to make mechanistic predictions. We used genetic epistasis to test some of these predictions, uncovering a novel transcriptional regulator, sup-37, that works alongside DAF-16/FOXO. We present a framework with predictive power that can accelerate discovery in C. elegans and potentially humans.

Automated summary

We designed a wisdom-of-the-crowds GRN inference pipeline coupled with complex network analysis to understand the organizational principles governing gene regulation in long-lived glp-1/Notch Caenorhabdities legans. Through screening 80% of regulators, we discovered 50 new aging genes, with 86% having human orthologues. The core genes essential for longevity, including those involved in insulin-like signaling (ILS), were found, indicating the predictive functionality of the GRN structure.