Biology subjects

Stoll, M.

Publications and source records attributed to Stoll, M..

4 recordsLinked to original sources

bioRxiv2021

C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100A8 and S100A9

The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of s100a8 and s100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout based screening approach in immortalized murine monocytes we identified the transcription factor C/EBP{delta} as a central regulator of S100A8 and S100A9 expression. S100a8 and S100a9 expression was further controlled by the C/EBP{delta}-antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBP{delta}-binding sites within s100a8 and s100a9 promoter regions, and demonstrated that C/EBP{delta}-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBP{delta} as a novel regulator of S100A8 and S100A9 expression. Therefore, C/EBP{delta} represents a promising target for modulation of inflammatory conditions that are characterised by S100A8 and S100A9 overexpression.

cell biology↗

bioRxiv2021

A genetic variant alters the secondary structure of the lncRNA H19 and is associated with Dilated Cardiomyopathy

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

genetics↗

bioRxiv2021

Evolutionarily conserved transcriptional landscape of the heart defining the chamber specific physiology

Cardiovascular disease (CVD) remains the leading cause of death worldwide. A deeper characterization of the regional transcription patterns within different heart chambers may aid to improve our understanding of the molecular mechanisms involved in the function of the heart as well as our ability to develop novel therapeutic strategies. Here, we determined differentially expressed protein coding, long non-coding (lncRNA) and circular RNA (CircRNA) genes within various heart chambers across seven vertebrate species. We identified chamber specific genes, lncRNAs and pathways that are evolutionarily conserved in vertebrates. Further, we identified lncRNA homologs based on sequence, secondary structure, synteny and expressional conservation. Interestingly, most lncRNAs were found to be syntenically conserved. Various factors affect the co-expression patterns of transcripts including (i) genomic overlap, (ii) strandedness and (iii) transcript biotype. We also provide a catalogue of CircRNAs which are abundantly expressed across vertebrate hearts. Finally, we established a repository called EvoACTG (http://evoactg.uni-muenster.de/), which provides information about the conserved expression patterns for both PC genes and non-coding RNAs (ncRNAs) in the various heart chambers, and may serve as a community resource for investigators interested in the (patho)-physiology of CVD. We believe that this study will inform researchers working in the field of cardiovascular biology to explore the conserved yet intertwined nature of both coding and non-coding cardiac transcriptome across various popular model organisms in CVD research.

genomics↗

bioRxiv2021

Diversity and prevalence of colibactin- and yersiniabactin encoding mobile genetic elements in enterobacterial populations: insights into evolution and co-existence of two bacterial secondary metabolite determinants

1 AbstractThe bacterial genotoxin colibactin interferes with the eukaryotic cell cycle by causing double-stranded DNA breaks. It has been linked to bacterially induced colorectal cancer in humans. Colibactin is encoded by a 54-kb genomic region in Enterobacteriaceae. The colibactin genes commonly co-occur with the yersiniabactin biosynthetic determinant. Investigating the prevalence and sequence diversity of the colibactin determinant and its linkage to the yersiniabactin operon in prokaryotic genomes, we discovered mainly species-specific lineages of the colibactin determinant and classified three main structural settings of the colibactin-yersiniabactin genomic region in Enterobacteriaceae. The colibactin gene cluster has a similar but not identical evolutionary track to that of the yersiniabactin operon. Both determinants could have been acquired on several occasions and/or exchanged independently between enterobacteria by horizontal gene transfer. Integrative and conjugative elements play(ed) a central role in the evolution and structural diversity of the colibactin-yersiniabactin genomic region. Addition of an activating and regulating module (clbAR) to the biosynthesis and transport module (clbB-S) represents the most recent step in the evolution of the colibactin determinant. In a first attempt to correlate colibactin expression with individual lineages of colibactin determinants and different bacterial genetic backgrounds, we compared colibactin expression of selected enterobacterial isolates in vitro. Colibactin production in the tested Klebsiella spp. and Citrobacter koseri strains was more homogeneous and generally higher than that in most of the E. coli isolates studied. Our results improve the understanding of the diversity of colibactin determinants and its expression level, and may contribute to risk assessment of colibactin-producing enterobacteria.

microbiology↗