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

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.

Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal cancers

“…In contrast, the CDS1-CDS2 SLI demonstrated signi cant cancer speci city. The high SLI score for CDS1-CDS2 is consistent with other analyses and screens scoring CDS1-CDS2 as a candidate synthetic lethal pair, but to our knowledge this has not yet been pursued 18,30,32,40 . CDS1 and CDS2 are enzymes that are conserved in plants and yeast.…”

The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

“…Thus, the observation that HAPSTR2 can still complex with HUWE1 independent from HAPSTR1 suggests the possibility of HAPSTR2 replacing HAPSTR1 in the HAPSTR-HUWE1 complex in contexts where HAPSTR1 is compromised. This notion of paralog buffering has been observed with many other paralogous gene pairs 17 – 19 and is supported by our signaling and functional experiments. We note here a distinction between buffering of HAPSTR1 loss via constitutive expression of its paralog and genetic compensation, whereby one paralog is selectively expressed in response to the loss of the other 36 – 38 .…”

“…This observation suggests that HAPSTR2 expression augments basal HAPSTR-HUWE1 pathway function. We then assessed whether HAPSTR2 can compensate for HAPSTR1 loss, a phenomenon called paralog buffering which is thought to safeguard organismal fitness 17 – 19 . Indeed, HAPSTR2 expression either fully or partially rescued the effects of HAPSTR1 loss on model signaling proteins (Fig.…”

Complex consequences of disturbance on canopy plant communities of world forests: a review and synthesis

“…In this synthesis, I used the DPSIR framework to organize and synthesize the current body of work on EM disturbance and its impacts, but other theoretical frameworks originating within and outside ecosystem ecology could also be explored, described by Gough and Buma (2023). Such approaches include: multidimensional stability (Hillebrand et al ., 2018; Mathes et al ., 2021); disturbance legacies (Huston, 2014); tipping points, thresholds, and alternate stable states (Scheffer & Carpenter, 2003); landscape dynamics (Turner, 2010); and functional buffering (Lin et al ., 2022). As the pool of studies on this topic grows and matures to have more consistent measures, application of these other frameworks would be an exciting and useful task for the future.…”