Cell systems最新文献

Recent biological studies have been revolutionized in scale and granularity by multiplex and high-throughput assays. Profiling cell responses across several experimental parameters, such as perturbations, time, and genetic contexts, leads to richer and more generalizable findings. However, these multidimensional datasets necessitate a reevaluation of the conventional methods for their representation and analysis. Traditionally, experimental parameters are merged to flatten the data into a two-dimensional matrix, sacrificing crucial experiment context reflected by the structure. As Marshall McLuhan famously stated, "the medium is the message." In this work, we propose that the experiment structure is the medium in which subsequent analysis is performed, and the optimal choice of data representation must reflect the experiment structure. We review how tensor-structured analyses and decompositions can preserve this information. We contend that tensor methods are poised to become integral to the biomedical data sciences toolkit.

How do variations in nutrient levels influence cellular lifespan? A dynamical systems model of a core circuit involved in yeast aging suggests principles underlying lifespan extension observed at static and alternating glucose levels that are reminiscent of intermittent fasting regimens.

Evolution-based deep generative models represent an exciting direction in understanding and designing proteins. An open question is whether such models can learn specialized functional constraints that control fitness in specific biological contexts. Here, we examine the ability of generative models to produce synthetic versions of Src-homology 3 (SH3) domains that mediate signaling in the Sho1 osmotic stress response pathway of yeast. We show that a variational autoencoder (VAE) model produces artificial sequences that experimentally recapitulate the function of natural SH3 domains. More generally, the model organizes all fungal SH3 domains such that locality in the model latent space (but not simply locality in sequence space) enriches the design of synthetic orthologs and exposes non-obvious amino acid constraints distributed near and far from the SH3 ligand-binding site. The ability of generative models to design ortholog-like functions in vivo opens new avenues for engineering protein function in specific cellular contexts and environments.

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.

Single-cell transcriptomics reveals significant variations in transcriptional activity across cells. Yet, it remains challenging to identify mechanisms of transcription dynamics from static snapshots. It is thus still unknown what drives global transcription dynamics in single cells. We present a stochastic model of gene expression with cell size- and cell cycle-dependent rates in growing and dividing cells that harnesses temporal dimensions of single-cell RNA sequencing through metabolic labeling protocols and cel lcycle reporters. We develop a parallel and highly scalable approximate Bayesian computation method that corrects for technical variation and accurately quantifies absolute burst frequency, burst size, and degradation rate along the cell cycle at a transcriptome-wide scale. Using Bayesian model selection, we reveal scaling between transcription rates and cell size and unveil waves of gene regulation across the cell cycle-dependent transcriptome. Our study shows that stochastic modeling of dynamical correlations identifies global mechanisms of transcription regulation. A record of this paper's transparent peer review process is included in the supplemental information.

One snapshot of the peer review process for "Transcriptome data are insufficient to control false discoveries in regulatory network inference" (Kernfeld et al., 2024).¹.

Inference of causal transcriptional regulatory networks (TRNs) from transcriptomic data suffers notoriously from false positives. Approaches to control the false discovery rate (FDR), for example, via permutation, bootstrapping, or multivariate Gaussian distributions, suffer from several complications: difficulty in distinguishing direct from indirect regulation, nonlinear effects, and causal structure inference requiring "causal sufficiency," meaning experiments that are free of any unmeasured, confounding variables. Here, we use a recently developed statistical framework, model-X knockoffs, to control the FDR while accounting for indirect effects, nonlinear dose-response, and user-provided covariates. We adjust the procedure to estimate the FDR correctly even when measured against incomplete gold standards. However, benchmarking against chromatin immunoprecipitation (ChIP) and other gold standards reveals higher observed than reported FDR. This indicates that unmeasured confounding is a major driver of FDR in TRN inference. A record of this paper's transparent peer review process is included in the supplemental information.

Cellular longevity is regulated by both genetic and environmental factors. However, the interactions of these factors in the context of aging remain largely unclear. Here, we formulate a mathematical model for dynamic glucose modulation of a core gene circuit in yeast aging, which not only guided the design of pro-longevity interventions but also revealed the theoretical principles underlying these interventions. We introduce the dynamical systems theory to capture two general means for promoting longevity-the creation of a stable fixed point in the "healthy" state of the cell and the "dynamic stabilization" of the system around this healthy state through environmental oscillations. Guided by the model, we investigate how both of these can be experimentally realized by dynamically modulating environmental glucose levels. The results establish a paradigm for theoretically analyzing the trajectories and perturbations of aging that can be generalized to aging processes in diverse cell types and organisms.

Functional magnetic resonance imaging (fMRI) provides insights into cognitive processes with significant clinical potential. However, delays in brain region communication and dynamic variations are often overlooked in functional network studies. We demonstrate that networks extracted from fMRI cross-correlation matrices, considering time lags between signals, show remarkable reliability when focusing on statistical distributions of network properties. This reveals a robust brain functional connectivity pattern, featuring a sparse backbone of strong 0-lag correlations and weaker links capturing coordination at various time delays. This dynamic yet stable network architecture is consistent across rats, marmosets, and humans, as well as in electroencephalogram (EEG) data, indicating potential universality in brain dynamics. Second-order properties of the dynamic functional network reveal a remarkably stable hierarchy of functional correlations in both group-level comparisons and test-retest analyses. Validation using alcohol use disorder fMRI data uncovers broader shifts in network properties than previously reported, demonstrating the potential of this method for identifying disease biomarkers.

Transcription factors can promote gene expression through activation domains. Whole-genome screens have systematically mapped activation domains in transcription factors but not in non-transcription factor proteins (e.g., chromatin regulators and coactivators). To fill this knowledge gap, we employed the activation domain predictor PADDLE to analyze the proteomes of Arabidopsis thaliana and Saccharomyces cerevisiae. We screened 18,000 predicted activation domains from >800 non-transcription factor genes in both species, confirming that 89% of candidate proteins contain active fragments. Our work enables the annotation of hundreds of nuclear proteins as putative coactivators, many of which have never been ascribed any function in plants. Analysis of peptide sequence compositions reveals how the distribution of key amino acids dictates activity. Finally, we validated short, "universal" activation domains with comparable performance to state-of-the-art activation domains used for genome engineering. Our approach enables the genome-wide discovery and annotation of activation domains that can function across diverse eukaryotes.