Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Hao-Kuen Lin,Carolyn Dunlap,Jen-Hao Cheng,Sheng-Hong Chen,Chia-Chou Wu,Feng-Shu Hsieh

doi:10.1038/s41598-022-06813-4

Abstract

Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. However, the mechanism underlying functional buffering, particularly in multicellular organisms, remains largely elusive. Here, we proposed that functional buffering can be mediated via expression of buffering genes in specific cells and tissues, by which we named Cell-specific Expression-BUffering (CEBU). We developed an inference index (C-score) for CEBU by computing C-scores across 684 human cell lines using genome-wide CRISPR screens and transcriptomic RNA-seq. We report that C-score-identified putative buffering gene pairs are enriched for members of the same duplicated gene family, pathway, and protein complex. Furthermore, CEBU is especially prevalent in tissues of low regenerative capacity (e.g., bone and neuronal tissues) and is weakest in highly regenerative blood cells, linking functional buffering to tissue regeneration. Clinically, the buffering capacity enabled by CEBU can help predict patient survival for multiple cancers. Our results suggest CEBU as a potential buffering mechanism contributing to tissue homeostasis and cancer robustness in humans.

Highlights

Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty
In seeking an index to explore intrinsic buffering operated via constitutive gene expression, we postulated a buffering relationship whereby the essentiality of a buffered gene (G1) increases when expression of its buffering gene (G2) decreases across different human cell lines (Fig. 1)
This concept prompted the formulation of the cell-specific expression buffering mechanism, here named Cell-specific Expression-BUffering (CEBU), which can be quantitatively investigated by developing an inference index, C-score

Summary

Introduction

Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. Inactivation of one growth signaling pathway can lead to activation of others for the coordination of cell growth and survival[3,4] Such needs-based buffering genes have been documented as enabling unicellular/multicellular organisms to cope with environmental s tresses[3,8]. To explore CEBU as a potential buffering mechanism and to estimate buffering capability, we developed an inference index, the C-score, to identify putative gene pairs displaying CEBU This index calculates the adjusted correlation between expression of a buffering gene and the essentiality of the buffered gene (Fig. 1B), utilizing transcriptomics d ata[14] and genome-wide dependency data from the DepMap project[14,15] across 684 human cell lines.

Methods

Results

Conclusion