Biology subjects

Lagger, C.

Publications and source records attributed to Lagger, C..

4 recordsLinked to original sources

bioRxiv2026

Spike-in-normalised single-cell RNA-seq reveals cell-type-specific transcriptional repression during ageing

Transcriptome analyses are widely used for biomarker discovery and to gain insights into normal processes and diseases. Age-related changes in gene expression inferred from RNA-seq are typically reported relative to the transcriptome composition using library-size normalisation. As such, absolute changes in transcript abundance with age remain poorly characterised. Here, using external spike-in normalisation in the Tabula Muris Senis dataset, we quantify age-related variation in total mRNA content and gene expression across mouse cell types. We observe widespread changes in total mRNA abundance, with decreases predominantly in non-immune cell types and increases predominantly in immune cell types. In parallel, the number of genes expressed declines across most cell types, including immune populations. Differential expression analysis based on spike-in-normalised counts identifies genes consistently downregulated across cell types, enriched for functions in RNA metabolism and protein processing. Furthermore, genes downregulated during ageing and during proliferation arrest show partial overlap, suggesting that these transcriptional changes may share regulatory processes. Together, these results are consistent with a general repression of transcriptional and metabolic activity with age, modulated by immune-specific responses. HighlightsO_LITotal mRNA content decreases with age in several non-immune cell types and increases in most immune cell types. C_LIO_LIThe number of detected genes decreases with age in most cell types. C_LIO_LIGenes downregulated based on absolute normalisation are associated with RNA and protein metabolism. C_LIO_LIAgeing-associated transcriptional repression overlaps with gene expression programs linked to proliferation arrest. C_LI

genomics↗

bioRxiv2024

Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity

Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity ({beta}-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells. Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples. Genes regulating stress responses - including transcription factors and genes controlling chromatin accessibility - are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner. We propose that senescence cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, TFs, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.

bioinformatics↗

bioRxiv2024

Intensifying marine heatwaves and limited protection threaten global kelp forests

Kelp forests are one of the earths most productive ecosystems and are at the greatest risk from climate change, yet little is known regarding their future threats and current conservation status. By combining a global remote sensing dataset of floating kelp forests with climate data and projections, we find that exposure to projected marine heatwaves will increase [~]8 times compared to contemporary (2001-2020) exposure for intermediate climate scenarios. While exposure will intensify for all forests, climate refugia emerge for some southern hemisphere kelp forests, which have lower exposure to contemporary and projected marine heatwaves. Under these escalating threats, less than 3% of global kelp forests are currently within highly restrictive marine protected areas, the most effective conservation measure for providing climate resilience. Our findings emphasize the urgent need to increase the global protection of kelp forests and set bolder climate adaptation goals.

ecology↗

bioRxiv2021

scAgeCom: a murine atlas of age-related changes in intercellular communication inferred with the package scDiffCom

Dysregulation of intercellular communication is a well-established hallmark of aging. To better understand how this process contributes to the aging phenotype, we built scAgeCom, a comprehensive atlas presenting how cell-type to cell-type interactions vary with age in 23 mouse tissues. We first created an R package, scDiffCom, designed to perform differential intercellular communication analysis between two conditions of interest in any mouse or human single-cell RNA-seq dataset. The package relies on its own list of curated ligand-receptor interactions compiled from seven established studies. We applied this tool to single-cell transcriptomics data from the Tabula Muris Senis consortium and the Calico murine aging cell atlas. All the results can be accessed online, using a user-friendly, interactive web application (https://scagecom.org). The most widespread changes we observed include upregulation of immune system processes, inflammation and lipid metabolism, and downregulation of extracellular matrix organization, growth, development and angiogenesis. More specific interpretations are also provided.

bioinformatics↗