Biology subjects

Snabel, R. R.

Publications and source records attributed to Snabel, R. R..

4 recordsLinked to original sources

bioRxiv2026

Roles of Neuromedin-U and Endothelin-1 in human cardiac organoid differentiation

During recent years, many new culture methods have been established to generate cardiomyocytes, using signaling and patterning factors that play important roles in mammalian heart development. Here, we identify two additional pathways of interest using a cardiac differentiation roadmap that we have generated, involving the endothelin 1 receptor EDNRA gene, and the Neuromedin family signaling peptide gene NMU. Treatment with NMU had most effect in ventricular lineages where it normally is not abundantly expressed, leading to a significant shift from ventricular cardiomyocyte (vCM) differentiation to non-myocytes, as shown with reporters and cell type-specific markers, which was associated with an increased beating frequency. This was not observed in atrial cultures. Treating atrial cultures with endothelin 1 (ET-1, EDN1) increased the number of atrial cardiomyocytes (aCM), while reducing repolarization times, increasing the contraction frequencies and altering the patterns of action potential propagations across the tissue. In ventricular cultures, a reduction in ventricular cardiomyocyte (vCM) numbers was observed, suggesting a combinatorial effect of ET-1 and retinoic acid (RA) on cardiomyocyte differentiation. These results identify ET-1 and NMU as important signaling factors for cardiomyocyte differentiation and electrophysiology of cardiac organoids, with ET-1 enhancing aCM differentiation when added around the time of posteriorization of the second heart field. NMU added without RA reduces the number of vCMs in the culture while it changes the organoids to exhibit a more atrial-like beating frequency.

developmental biology↗

bioRxiv2025

DANSE: a pipeline for dynamic modelling of time-series multi-omics data

BackgroundUnderstanding time-dependent intracellular processes, such as cell differentiation, is key to developing new therapies for a wide range of diseases. Models that connect transcription factor activity to dynamic expression patterns are rare, despite the increased availability of time-series data. ResultsTo identify key regulators of time-dependent biological processes, we present the pipeline DANSE: Dynamics inference Algorithm on Networks Specified by Enhancers. Starting from multi-omics data, our pipeline constructs a data-driven mechanistic transcription factor (TF) network and subsequently defines a dynamic model based on this TF network. The combination of a TF network and a mechanistic model allows for the identification of a small set of key transcription factors predicted to drive the modelled biological process. We showcase the result of our pipeline by applying DANSE to two different datasets that describe iPSC differentiation. ConclusionsModels constructed using DANSE suggest testable hypotheses for the perturbation of gene expression, for example, knockdown or overexpression, that influence cell fate. In this way, DANSE is a powerful tool for generating novel hypotheses in a data-driven manner that take into account the dynamic nature of multi-omics time series data.

systems biology↗

bioRxiv2024

Single-cell roadmap of cardiac differentiation identifies roles for ZNF711 and retinoic acid in balanced epicardial and cardiomyocyte lineage commitment

Stem cell-based models of human heart tissue and cardiac differentiation employ monolayer and 3D organoid cultures with different properties, cell type composition, and maturity. Here we show how cardiac monolayer, embryoid body, and engineered heart tissue trajectories compare in a single-cell roadmap of atrial and ventricular differentiation conditions. Using a multiomic approach and gene-regulatory network inference, we identified regulators of the epicardial, atrial and ventricular cardiomyocyte lineages. We identified ZNF711 as a regulatory switch and safeguard for cardiomyocyte commitment. We show that ZNF711 ablation prevents cardiomyocyte differentiation in the absence of retinoic acid, causing progenitors to be diverted more prominently to epicardial and other lineages. Retinoic acid rescues this shift in lineage commitment and promotes atrial cardiomyocyte differentiation by regulation of shared and complementary target genes, showing an interplay between ZNF711 and retinoic acid in cardiac lineage commitment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/588683v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e3733forg.highwire.dtl.DTLVardef@a34e61org.highwire.dtl.DTLVardef@16eccdcorg.highwire.dtl.DTLVardef@14bb7a5_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIWe present an atlas of cardiac differentiation under different culture conditions, showing progenitor trajectories and cell states reminiscent of the fetal heart. C_LIO_LIMultiome and chromatin accessibility analysis identified candidate regulators of cardiomyocyte and non-cardiomyocyte lineages. C_LIO_LIDistinct trajectories of lineage commitment and differentiation under different culture conditions shows plasticity of first and second heart field progenitors and different ratios of cardiomyocyte and non-myocyte lineages. C_LIO_LIZNF711 is required for balanced commitment to epicardial and ventricular cardiomyocyte lineages. Retinoic acid rescues a requirement for ZNF711 in cardiomyocyte differentiation, promoting both atrial cardiomyocyte and epicardial differentiation. C_LI

developmental biology↗

bioRxiv2022

ONECUT2 restricts Microfold cell numbers in the small intestine; a multi-omics study

Microfold (M) cells reside in the intestinal epithelium of Peyers patches. Their unique ability to take up and transport antigens from the intestinal lumen to the underlying lymphoid tissue is key in the regulation of the gut-associated immune response. Here, we applied a (single-cell) multi-omics approach to investigate the molecular mechanisms that drive M cell differentiation in mouse small intestinal organoids. We generated a comprehensive profile of chromatin accessibility changes and transcription factor dynamics during in vitro M cell differentiation, allowing us to uncover numerous cell type-specific regulatory elements and associated transcription factors. Single-cell RNA sequencing resulted in the identification of an M cell precursor population. Our new computational tool SCEPIA determined that these precursor cells were characterized by high expression of and motif activity for the transcription factor ONECUT2. Subsequent perturbation experiments revealed that ONECUT2 acts downstream of the RANK/RANKL signalling to support Enterocyte differentiation and restrict M cell lineage specification in vitro and in vivo, thereby regulating mucosal immunity. This study provides a useful blueprint for future investigations of cell fate switches in the intestinal epithelium.

molecular biology↗