Biology subjects

Severinov, D.

Publications and source records attributed to Severinov, D..

2 recordsLinked to original sources

bioRxiv2026

Baseline regulatory programs in larval and adult neural progenitors converge towards an injury-induced state after spinal cord injury

Regeneration after spinal cord injury requires progenitor cells to convert injury-associated signals into coordinated remodeling of gene regulatory programs. Mammalian spinal progenitors show limited neurogenic output after injury, whereas zebrafish regenerate spinal neurons and recover motor function. To investigate the regulatory changes that allow ependymo-radial glia (ERG) cells, the progenitor cells of the zebrafish spinal cord, to generate new neurons, we combined single-nucleus gene expression and chromatin accessibility profiling across embryonic, larval, and adult stages with topic-based gene regulatory network (GRN) inference. We found that larval and adult ERGs enter the injury response from distinct regulatory baselines: larval progenitors are characterized by a gliogenic program, whereas adult progenitors maintain a comparatively quiescent state. Following injury, both populations gradually change their baseline programs and shift towards a lesion-associated module marked by stress-responsive and chromatin-associated regulators, including jun, hmga1a, hmga2, ybx1, and foxj1a. The shift away from homeostatic states is supported by decreased expression of the Notch-associated regulators nuclear factor I A (nfia) and hey1 in larvae, while in adults, downregulation of the same nuclear factor and other TFs such as bhlhe41 is associated with quiescence exit. Pathway analysis showed stage-specific alterations after injury, characterized predominantly by extracellular signaling and cytoskeletal reorganization in larvae and by metabolic and translational remodeling in adults. Despite divergence from the homeostatic states, injury-induced larval and adult GRNs remain distinct from embryonic hERG regulatory programs. Thus, larval and adult progenitors follow different trajectories from their baselines towards a related lesion-reactive state, in which shared regeneration-associated features are acquired within respective contexts.

bioinformatics↗

bioRxiv2025

Tumor clone dynamics in gastro-esophageal cancer organoids reveal a non-genetic memory of neoadjuvant chemotherapy via downregulation of NFκB signaling

Adenocarcinomas of the gastroesophageal junction exhibit genetic and non-genetic heterogeneity that impact clinical outcomes, though the underlying mechanisms behind drug resistance remain poorly understood. We integrated bulk whole-genome sequencing (WGS) and single cell RNA sequencing (scRNA-seq) data from patient-derived organoid lines generated from drug resistant gastric tumors of three patients before and after chemotherapy with FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel), investigating both in vivo and ex vivo treatment effects. We found that inter-patient variability of gene expression exceeds intra-patient differences and predominantly shapes the expression profiles. Integration of WGS-inferred cancer phylogenies with scRNA-seq data allowed us to associate genetic clones with the individual cells transcriptional program and to track the genetic and transcriptomic history of dominant genetic clones in post-treatment samples relative to the corresponding primary tumor. Notably, in vivo treated samples appeared to be transcriptionally distinct from the untreated counterparts, marked by sustained NF-{kappa}B down-regulation, which suggests that they retain an immune-mediated imprint of the prior therapy. Changes in the clonal composition of a tumor alone cannot explain the post-chemotherapy NF-{kappa}B-associated transcriptional reprogramming. Instead, non-genetic mechanisms shape the altered transcriptomic landscape, particularly a distinct subpopulation of epithelial cells that specifically express pro-inflammatory cytokines, key components of the NF-{kappa}B regulatory network. These observations support a model of transcriptional reprogramming after FLOT treatment, which is most likely independent of genetic evolution and consequently potentially reversible. Downregulated NF-{kappa}B signaling may thus represent a candidate pathway change for predictive response assessment and/or NF-{kappa}B-stimulating co-therapeutic strategies to overcome FLOT resistance.

cancer biology↗