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

Identifier:  imarina:9243284

Handle: https://hdl.handle.net/20.500.11797/imarina9243284

Authors:  Suriyalaksh, M; Raimondi, C; Mains, A; Segonds-Pichon, A; Mukhtar, S; Murdoch, S; Aldunate, R; Krueger, F; Guimera, R; Andrews, S; Sales-Pardo, M; Casanueva, O

Abstract:
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 Caenorhabditis elegans. The GRN has three layers (input, core, and output) and is topologically equivalent to bow-tie/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.