Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.02.27.708233

The Translatome of Senescent Cells Revealed by Ribosome Profiling

Kalekar, R. L.·Kelsey, M. M. G.·Sedivy, J. M.
View original source ↗Export metadata ↓

Abstract

Cellular senescence drives aging-related tissue dysfunction through the senescence-associated secretory phenotype (SASP), an inflammatory secretome linked to retrotransposable element (RTE) derepression. Transcriptomic and proteomic approaches have extensively characterized the senescence program, but key gaps remain: transcript abundance is a poor proxy for protein output, limited proteomic depth misses low-abundance proteins, and the highly repetitive sequences of RTEs compromise locus-level peptide attribution. To bridge these gaps, we used AHARIBO (AzidoHomoAlanine-mediated RIBOsome isolation), which captures actively translated full-length mRNAs, to profile the translatome of proliferating, senescent, and late-senescent human fibroblasts. Comparing these ribosome-associated transcripts with the total mRNA pool revealed marked post-transcriptional regulation of key senescence programs. Inflammatory SASP components were translationally depleted in senescence, and these transcripts were enriched for AU-rich element-binding protein motifs, including the ZFP36 family, implicating these proteins in post-transcriptional gating of inflammatory signaling. Transcriptome-wide, translational efficiency was associated with 3UTR GC content and specific RNA-binding protein and microRNA (miRNA) motifs. We also observed a striking wobble-position codon bias: a proliferation-specific program favoring A/U-ending codons collapsed in senescence, disproportionately affecting cell-cycle and proliferation gene sets. By pairing AHARIBO with a sample-specific reference genome incorporating non-reference L1 insertions, we resolved translation of individual L1 loci and identified two intact L1HS elements with sustained activation in senescence. One of these, L1HS_14q23.2_3, independently identified in multiple experiments, emerges as a candidate intact L1 locus for producing inflammatory cDNA species. These findings implicate translational control as an important regulatory layer shaping the senescent program.

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kalekar, R. L., Kelsey, M. M. G., Sedivy, J. M.. 2026-03-01. The Translatome of Senescent Cells Revealed by Ribosome Profiling. https://doi.org/10.64898/2026.02.27.708233

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity

The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.

cell biology↗
bioRxiv2026

Nucleosome Core Allostery Governs Chromatin Recognition and Cell Fate

Nucleosomes regulate chromatin folding, accessibility, and factor recruitment. Current models primarily attribute these functions to histone tail modifications, while the core is largely viewed as a structural scaffold. Yet subtle changes within the nucleosome core can produce profound functional consequences, and the mechanisms underlying these effects remain unclear. Here, we describe nucleosome core allostery as a fundamental principle of chromatin regulation that amplifies the impact of minimal nucleosome variations. Leveraging natural differences between H2A.Z variants, we show that the nucleosome core encodes distinct conformational dynamics that propagate allosterically, thereby controlling nucleosome accessibility and recognition by chromatin factors. As a result, a single buried amino acid substitution alone is sufficient to reprogram nucleosome dynamics and bias cell identity. Our findings establish the nucleosome core as an allosteric regulatory module and provide a generalizable framework for how subtle variation within nucleosomes is amplified into diverse biological outcomes in development and disease.

cell biology↗
bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗