Biology subjects

Schopp, M.

Publications and source records attributed to Schopp, M..

3 recordsLinked to original sources

bioRxiv2025

Cumulative TF binding and H3K27 Acetylation drive enhancer activation frequency

In eukaryotes, transcription factors (TFs) must continuously compete with nucleosomes to access their binding sites, leading to cell-to-cell variability in chromatin accessibility at regulatory regions. Although critical to understand enhancer function in transcription, the mechanisms that define how frequently an enhancer is active in a cell population remain unclear. Here, we used single molecule footprinting to quantify the frequency at which chromatin is accessible at enhancers in response to TF perturbations, and changes of their chromatin environment. We find that individually most TFs open chromatin in a small fraction of the cells, and that cumulative TF binding controls enhancers activation frequency. Moreover, testing the functionality of hundreds of enhancers when inserted at an ectopic genomic location identifies H3K27Ac as a chromatin mark required for their full activation. Our data support a model where enhancer activation frequency depends on the cumulative function of multiple TFs, enhanced by activating chromatin marks.

molecular biology↗

bioRxiv2023

An interactive cellular ecosystem blocks epithelial transformation in naked mole-rat

Long-lived species suppress cancer despite accumulating somatic mutations throughout life, but how this is achieved in renewing tissues remains unclear. Here, we show that naked mole-rat skin uncouples high cellular turnover from cancer risk through coordinated epithelial and stromal mechanisms that constrain clonal outgrowth and suppress tumor-promoting inflammation. Despite elevated epidermal proliferation and mutational burden, naked mole-rat skin maintains tissue integrity through an expanded pool of early committed progenitor (hybrid) cells and replication-coupled genome maintenance pathways. Under chronic carcinogenic stress, undifferentiated basal cells replenish the hybrid progenitor pool. This dilutes initiated clones and permits only limited selective expansion of rare cancer gene-mutant clones. Depletion of the hybrid compartment shifts this protective state toward clonal expansion and inflammatory activation. These expanding clones are further constrained by a highly tumor-suppressive stromal microenvironment, driven by fibroblasts that adopt a metabolically restricted, non-inflammatory program. Together, our data uncover a multi-layered tumor-suppressive strategy that couples turnover-driven regeneration with an anti-permissive stromal niche to prevent malignant progression under mutagenic stress.

cancer biology↗

bioRxiv2019

Renewal theory provides a universal quantitative framework to characterise the continuous regeneration of rotational events in cardiac fibrillation

BackgroundCardiac fibrillation is thought to be maintained by rotational activity, with pivoting regions called phase singularities (PSs). Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of rotors in fibrillation.\n\nObjectiveWe conducted a multi-modality, multi-species study of AF/VF under the hypothesis that PS formation/destruction in fibrillation can be modelled as self-regenerating renewal processes, producing exponential distributions of inter-event times governed by constant rate-parameters defined by the prevailing properties of the system.\n\nMethodsPS formation/destruction was studied and cross-validated in 5 models, using basket recordings and optical mapping from: i) human persistent AF (n = 20), ii) tachypaced sheep AF (n = 5), iii) rat AF (n = 4), iv) rat VF (n = 11) and v) computer simulated AF (SIM). Hilbert phase maps were constructed. PS lifetime data were fitted by exponential probability distribution functions (PDFs) computed using maximum entropy theory, and the rate parameter ({lambda}) determined. A systematic review was conducted to cross-validate with source data from literature.\n\nResultsPS destruction/formation distributions showed good fits to an exponential in all systems (R2 [≥] 0.90). In humans,{lambda} = 4.6%/ms (95%CI,4.3,4.9)), sheep 4.4%/ms (95%CI,4.1,4.7)), rat AF 38%/ms (95%CI,22,55), rat VF 46%/ms (95%CI,31.2,60.2) and SIM 5.4%/ms (95%CI,4.1,6.7). All PS distributions identified through systematic review were exponential with {lambda} comparable to experimental data.\n\nConclusionThese results provide a universal quantitative framework to explain rotor formation and destruction in AF/VF, and a platform for therapeutic advances in cardiac fibrillation.

physiology↗