Biology subjects

Kaspar, S.

Publications and source records attributed to Kaspar, S..

3 recordsLinked to original sources

bioRxiv2024

Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression

Kidney fibrosis, characterized by excessive extracellular matrix deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. This study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFR{beta}+ mesenchymal cells aimed at unraveling disease mechanisms. Using transcriptomics, proteomics, phosphoproteomics, and secretomics we quantified over 14,000 biomolecules across seven time points following TGF-{beta} stimulation. This revealed distinct temporal patterns in the expression and activity of known and potential kidney fibrosis markers and modulators. Data integration resulted in time-resolved multi-omic network models which allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and regulatory mechanisms underlying kidney fibrosis. In particular, we show that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a resource to be further leveraged by the community. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/618507v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@d2bfaborg.highwire.dtl.DTLVardef@257d34org.highwire.dtl.DTLVardef@13f06f3org.highwire.dtl.DTLVardef@e16e6c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

systems biology↗

bioRxiv2024

Induction of territorial behavior and dominance hierarchies in laboratory mice

Territorial behaviors comprise a set of coordinated actions and response patterns found across animal species that promote the exclusive access to resources. House mice are highly territorial with a subset of males consistently attacking and chasing competing males to expel them from their territories and performing urine marking behaviors to signal the extent of their territories. Natural variation in territorial behaviors within a mouse colony leads to the formation of dominance hierarchies in which subordinate males can reside within the territory of a dominant male. While the full repertoire of such territorial behaviors and hierarchies has been extensively studied in wild-derived mice in semi-natural enclosures, so far they have not been established in the smaller enclosures and with the genetically-defined laboratory strains required for the application of neural recording and manipulation methods. Here, we present a protocol to induce an extensive repertoire of territorial behaviors in small enclosures in laboratory mice, including a method for the simultaneous tracking of urine marking behavior in mouse pairs. Using this protocol we describe the emergence of robust dominant-subordinate hierarchies between pairs of CD1 outbred or CD1xB6 F1 hybrid mice, but unexpectedly not in C57BL/6 inbred animals. Our behavioral paradigm opens the door for neurocircuit studies of territorial behaviors and social hierarchy in the laboratory.

animal behavior and cognition↗

bioRxiv2022

Single molecule multi-omics reveals context-dependent regulation of enhancers by DNA methylation

Enhancers are cis-regulatory elements that control the establishment of cell identities during development. In mammals, enhancer activation is tightly coupled with local DNA demethylation. Yet, whether this epigenetic remodelling is necessary for enhancer activation is unknown. Here, we developed a single molecule multi-omics approach to measure chromatin accessibility and transcription factor binding as a function of the presence of methylation on the same DNA molecules. We leveraged natural epigenetic heterogeneity at active enhancers to test the impact of DNA methylation on their activity in multiple cell lineages. While reduction of DNA methylation appears dispensable for the activity of most enhancers, we identify a class of cell-type-specific enhancers where presence of DNA methylation antagonises the binding of transcription factors. Genetic perturbations reveal that chromatin accessibility and transcription factor binding are a direct function of active demethylation at these loci. Thus, in addition to safeguarding the genome from spurious activation, DNA methylation directly controls transcription factor occupancy at cell-type-specific active enhancers.

genomics↗