Biology subjects

Zimmer-Bensch, G.

Publications and source records attributed to Zimmer-Bensch, G..

3 recordsLinked to original sources

bioRxiv2026

A new set of DNA methylation variants in the human genome show predominant tissue specificity and sensitivity to reprogramming with a potential for disease susceptibility.

Analyses of 3,370 normal human tissues of ectodermal, endodermal and mesodermal origins identified 12,587 regions averaging [~]585 bp with significant differences in DNA methylation levels within identical tissues. These methylation variants (MeVars) occurred in 8,037 genes enriched in neurological disorders and cancers of which, majority were tissue-specific rather than being systemic. This somatic variation was reduced by reprogramming in vitro into iPSCs and in vivo during spermatogenesis. Analysis of prefrontal cortices showed a higher incidence of MeVars in the candidate genes in controls than schizophrenia patients wherein a subset showed significantly altered transcript levels. Similar effects were observed for oral tissues and skin fibroblast cells. MeVars showed significant association with SINE1, simple and low complexity repeats, H3K27me3, H3k9me3 and H3K4me1 modifications and EZH2, SUZ12 and REST binding sites. Collectively, MeVars have postzygotic origins with an ability to reset during reprogramming, adding a new dimension in the form of epigenetic diversity and its relevance to disease susceptibility in humans.

bioinformatics↗

bioRxiv2023

EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to the Ncam1 promoter via lncRNA/DNA triplex formation

Cell-cell communication is mediated by membrane receptors and their cognate ligands, such as the Eph/ephrin system, and dictates physiological processes, including cell proliferation and migration. However, whether and how Eph/ephrin signaling culminates in transcriptional regulation is largely unknown. Epigenetic mechanisms are key for integrating external "signals", e.g., from neighboring cells, into the transcriptome. We have previously reported that ephrinA5 stimulation of immortalized cerebellar granule (CB) cells elicits transcriptional changes of lncRNAs and protein-coding genes. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate the interaction of lncRNA with protein-coding genes by the combined power of in silico modeling of RNA/DNA interactions and respective wet lab approaches, in the context of ephrinA5-dependent regulation of cellular motility. We found that Snhg15, a cancer-related lncRNA, forms a triplex structure with the Ncam1 promoter and interacts with DNMT1. EphrinA5 stimulation leads to reduced Snhg15 expression, diminished Snhg15/DNMT1 interaction and decreased DNMT1 association with the Ncam1 promoter. These findings can explain the attenuated Ncam1 promoter methylation and elevated Ncam1 expression that in turn elicits decreased cell motility of CB cells. Hence, we propose that ephrinA5 influences gene transcription via lncRNA-targeted DNA methylation underlying the regulation of cellular motility.

molecular biology↗

bioRxiv2020

DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons

Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders. Molecular mechanisms that exert epigenetic control of gene expression, contribute to age-associated neuronal impairments. Both DNA methylation, mediated by DNA methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of cortical inhibitory interneurons. Deletion of Dnmt1 in parvalbumin-positive interneurons attenuates their age-related decline in the cerebral cortex. Moreover, DNMT1-deficient mice show improved somatomotor performance and reduced aging-associated transcriptional changes. A decline in the proteostasis network, responsible for the proper degradation and removal of defective proteins, is suggested to be essentially implicated in age- and disease-related neurodegeneration. Our data suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the proteostasis network during life-time.

neuroscience↗