Biology subjects

Guenther, A.

Publications and source records attributed to Guenther, A..

24 records · Page 2Linked to original sources

bioRxiv2020

Positioning of nucleosomes containing γ-H2AXprecedes active DNA demethylation and transcription initiation

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 ({gamma}-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome.

molecular biology↗

bioRxiv2020

Temporal and spatial dynamics of peat microbiomes in drained and rewetted soils of three temperate peatlands

In the last decades, rewetting of drained peatlands is on the rise worldwide, to restore the significant carbon sink function. Rewetted peatlands differ substantially from their pristine counterparts and can, thus, be considered as novel ecosystems. Despite the increasing understanding of peat microbiomes, little is known about the seasonal dynamics and network interactions of the microbial communities in these novel ecosystems, especially in rewetted groundwater-fed peatlands, i.e. fens. Here, we investigated the seasonal dynamics in both prokaryotic and eukaryotic microbiomes in three common types of fens in Northern Germany, namely percolation fen, alder forest and coastal fen. The eukaryotic microbiomes, including fungi, protists and metazoa, showed significant changes of their community structures across the seasons in contrast to largely unaffected prokaryotic microbiomes. The co-occurrence network in the summer showed a distinct topology compared to networks in the other seasons, which was driven by the increased connections among protists, as well as between protists and the other microbial groups. Our results also indicated that the dynamics in eukaryotic microbiomes differed between fen types, specifically in terms of saprotrophs, arbuscular mycorrhiza and grazers of bacteria. Our study provides the insight that microbial eukaryotes mainly define the seasonal dynamics of microbiomes in rewetted fen peatlands. Accordingly, future research should unravel the importance of eukaryotes for biogeochemical processes, especially the under-characterized protists and metazoa, in these novel yet poorly understood ecosystems.

microbiology↗

bioRxiv2019

Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibition

Alveolar epithelial cell type II (AEC2) injury underlies idiopathic pulmonary fibrosis (IPF). Here we show increased Notch1 signaling in AEC2s in human IPF and IPF models, causing enhanced proliferation and de-differentiation of AEC2s. As a result, we observed defective surfactant protein (SP)-B/C processing, elevated alveolar surface tension, repetitive alveolar collapse and development of lung fibrosis. Similar changes were encountered upon pharmacological inhibition of SP-B/C processing in vivo by pepstatin A. Inhibition of Notch signaling in cultured human IPF precision cut lung slices improved surfactant processing capacity of AEC2s and reversed fibrosis. Notch1 therefore offers as novel therapeutic target.\n\nOne sentence summaryNotch1 inhibition restores alveolar epithelial differentiation and surface tension and reverses matrix deposition in lung fibrosis

cell biology↗

bioRxiv2018

Copy number variation in small nucleolar RNAs regulates personality behavior

The Prader-Willi Syndrome (PWS) gene region is an imprinted gene complex involved in behavioral, metabolic and osteogenic functions. We have analyzed here the variation of two families of regulatory small nucleolar RNAs (SNORD115 and SNORD116) that are coded within the PWS and are expressed from the paternal chromosome. They are organized in two tandemly repeated clusters which are naturally copy number variable between individuals. We find that the copy numbers at these loci correlate with repeatable individual test scores for anxiety that are considered to constitute a component of the "personality" of individuals. We show this for different populations and species of mice, cavies and for the anxiety component of personality tests in humans. This is also the case for an inbred mouse strain (C57Bl6) implying that copy number variation creates phenotypic variability even in an isogenic background. In transcriptome data from brain samples of this strain we find SNORD copy-number correlated regulation of target genes that are known to be involved in influencing behavior. SNORD115 has previously been suggested to regulate splicing of the serotonin receptor Htr2c and we confirm this in our data. For SNORD116 we provide evidence that it regulates the expression level of the chromatin regulator Ankrd11, which itself regulates GABA receptors, metabolic pathways, cell differentiation and osteogenesis. Intriguingly, we find that craniofacial shapes in mice correlate also with SNORD116 copy numbers. New copy number variants are generated at very high rates in mice, possibly at every generation, explaining why conventional genetic mapping could not detect this association. Our results suggest that the variable dosage of two regulatory RNAs are major determinants of individual behavioral differences and correlated traits in mammals.

evolutionary biology↗

bioRxiv2018

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Idiopathic pulmonary fibrosis is a fatal, incurable lung disease in which the intricate alveolar network of the human lung is progressively replaced by fibrotic scars, eventually leading to respiratory failure. Myofibroblasts are the effector cells that lead to abnormal deposition of extracellular matrix proteins and therefore mediate fibrotic disease not only in the lung but also in other organs. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug, metformin, exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGF{beta}1 action, suppressing collagen formation, activating PPAR{gamma} signaling and inducing lipogenic differentiation in lung myofibroblasts derived from human patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-tolipofibroblast transdifferentiation. Detailed pathway analysis showed that the reduction of collagen synthesis was largely AMPK-dependent, whereas the transdifferentiation of myo- to lipofibroblasts occurred in a BMP2-PPAR{gamma}-dependent fashion and was largely AMPK-independent. Our data report an unprecedented role for metformin in lung fibrosis, thus warranting further therapeutic evaluation.

cell biology↗

bioRxiv2018

Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

developmental biology↗