Biology subjects

Elston, T.

Publications and source records attributed to Elston, T..

6 recordsLinked to original sources

bioRxiv2026

TDP-43 Sustains Satellite Cells to Maintain and Regenerate Skeletal Muscle

Skeletal muscle satellite cells, residing between the myofiber plasma membrane and the surrounding basement membrane, maintain and repair skeletal muscle throughout life. Typically quiescent, satellite cells can transition into a reversible alert state (GAlert) that primes them for rapid activation to maintain or repair muscle. From GAlert, SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of GAlert SCs even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports expression of stress response-associated transcripts during the quiescent-to-GAlert transition, and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of satellite cell survival as satellite cells activate and establish a TDP-43 requirement for maintaining and repairing skeletal muscle.

cell biology↗

bioRxiv2025

Extrachromosomal DNA Gives Cancer a New Evolutionary Pathway

During tumor progression, it has been assumed that individual cells that have acquired advantageous mutations overtake the population. Cancers driven by extrachromosomal DNA (ecDNA) do not follow this paradigm. Instead, these tumors have a spectrum of oncogene copy numbers across cells, and graded ecDNA variation may function as a form of bet-hedging that equips tumors with a broad range of phenotypes. Using imaging, single-cell multiomics, and multiplexed proteomics, we systematically characterized ecDNA levels across thousands of single cells. Higher ecDNA dosage produces proportional changes in transcript abundance, chromatin accessibility, protein levels, cell-cycle progression, and proliferation. Genes amplified on ecDNA exhibit distinct transcriptional scaling regimes that shift when the same genes are reintegrated into chromosomal homogeneous staining regions. When we experimentally disrupted the continuum of ecDNA dosage by sorting cells into low- and high-copy number states, the population rapidly recovered its original, continuous distribution. Our time-course data, live-cell imaging, and stochastic models collectively show that restoring this spectrum is an active, deterministic process rather than the passive outcome of random segregation. Together, these findings position ecDNA-mediated expression as a distinct evolutionary mechanism that endows tumors with rapid, population-level adaptability. These findings offer insight into why ecDNA-driven cancers are among the most aggressive and treatment-resistant.

genomics↗

bioRxiv2025

Local collective memory from ratiometric signaling outperforms cellular gradient sensing limits

Cells excel at interpreting noisy chemical gradients to guide fertilization, development, and immune responses, but the mechanisms underlying this remarkable ability remain poorly understood. Previous work showed that some G protein signaling pathways can overcome challenges from uneven receptor distribution by using a ratiometric signaling strategy. In this mechanism, G proteins receive information from both bound and unbound receptors, unlike classical signaling where only bound receptors contribute. Here, we show that ratiometric signaling also provides an unexpected ability to suppress noise from low receptor numbers. The benefit stems from each G protein remembering the last receptor state it encountered, so that at any instant, ratiometric G protein collectives reflect time-averaged receptor activity. Unlike classical signaling, this averaging remains unbiased and accurate across the varying ligand concentrations present in a spatial gradient. Using theory and simulations, we demonstrate that this averaging mechanism allows cells to surpass theoretical limits for gradient detection from instantaneous receptor information alone. Our findings reveal how ratiometric biochemical architectures enable robust temporal integration across spatially varying signals, providing cells with enhanced directional accuracy under noisy conditions.

biophysics↗

bioRxiv2021

RNA-BINDING PROTEINS DIRECT MYOGENIC CELL FATE DECISIONS

RNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease. How ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single cell RNA-sequencing of regenerating skeletal muscle reveals that RBP expression, including numerous neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates to stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discover that the neuromuscular disease associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis controlling myogenic cell fate transitions during terminal differentiation. The timing of RBP expression specifies cell fate transitions by providing a layer of post-transcriptional regulation needed to coordinate stem cell fate decisions during complex tissue regeneration.

molecular biology↗

bioRxiv2020

Exploratory polarization facilitates mating partner selection in Saccharomyces cerevisiae

Yeast decode pheromone gradients to locate mating partners, providing a model for chemotropism. How yeast polarize toward a single partner in crowded environments is unclear. Initially, cells often polarize in unproductive directions, but then they relocate the polarity site until two partners polarity sites align, whereupon the cells "commit" to each other by stabilizing polarity to promote fusion. Here we address the role of the early mobile polarity sites. We found that commitment by either partner failed if just one partner was defective in generating, orienting, or stabilizing its mobile polarity sites. Mobile polarity sites were enriched for pheromone receptors and G proteins, and we suggest that such sites engage in an exploratory search of the local pheromone landscape, stabilizing only when they detect elevated pheromone levels. Mobile polarity sites were also enriched for pheromone secretion factors, and simulations suggest that only focal secretion at polarity sites would produce high pheromone concentrations at the partners polarity site, triggering commitment.

cell biology↗

bioRxiv2019

Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration

Skeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell (MuSC). During injury, and in diseased muscle, stem cells are engaged to replace or repair damaged muscle, which requires the stem cells to exit quiescence and expand, followed by differentiation to regenerate myofibers and self-renewal to replenish the stem cell population. Following an injury, little is known regarding the timing of MuSC (skeletal muscle stem cell) self-renewal, myoblast expansion or myoblast differentiation. To determine the timing and kinetics of these cell fate decisions, we employed DNA-based lineage tracing to label newly replicated cells and followed cell fates during skeletal muscle regeneration. MuSCs activate and expand as myoblasts rapidly following injury, where the majority differentiate into myonuclei, establishing the centrally located myonuclear pool. Re-establishing the majority MuSC pool by self-renewal occurs after 5 days post-muscle injury, accompanied by low levels of myonuclear accretion that generate only peripheral myonuclei. In aged mice, possessing [~]1/2 the number of MuSCs present in young adult mice, the timing of post injury MuSC self-renewal is delayed, and although MuSCs expansion as myoblasts in aged muscle is impaired, the number of MuSC unexpectedly recovers to young adult levels during regeneration. Following an induced muscle injury, we found that myonuclei are generated within the first four days post injury derived from myoblasts expanding from activated MuSCs. Only later during regeneration, from 5 d to 14 d post injury, is the MuSC pool replenished by self-renewal, accompanied by generation of peripheral myonuclei.

cell biology↗