Biology subjects

Thiecke, M. J.

Publications and source records attributed to Thiecke, M. J..

3 recordsLinked to original sources

bioRxiv2020

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

microbiology↗

bioRxiv2020

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics of chromosomal contacts of all human gene promoters upon rapid architectural protein degradation. We show that promoter contacts lost in these conditions tend to be long-range, with at least one interaction partner localising in the vicinity of topologically associated domain (TAD) boundaries. In contrast, many shorter-range chromosomal contacts, particularly those that connect active promoters with each other and with active enhancers remain unaffected by cohesin and CTCF depletion. We demonstrate that the effects of cohesin depletion on nascent transcription can be explained by changes in the connectivity of their enhancers. Jointly, these results provide a mechanistic explanation to the limited, but consistent effects of cohesin and CTCF on steady-state transcription and point towards the existence of alternative enhancer-promoter pairing mechanisms that are independent of these proteins.

genomics↗

bioRxiv2018

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients brains. ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.\n\nOne Sentence SummaryISRIB ameliorates ISR deregulation and clinical signs in VWM mice

neuroscience↗