Biology subjects

Strati, K.

Publications and source records attributed to Strati, K..

4 recordsLinked to original sources

bioRxiv2023

Oct4 is a gatekeeper of epithelial identity by regulating cytoskeletal dynamics in skin keratinocytes

Oct4 is a pioneer transcription factor regulating pluripotency. However, it is poorly known whether Oct4 has an impact on epidermal cells. We generated OCT4 knockout clonal cell lines using immortalized human skin keratinocytes to identify a functional role for the protein. Here we report that Oct4-deficient cells transitioned into a mesenchymal-like phenotype with enlarged size and shape, exhibited accelerated migratory behavior, decreased adhesion and appeared arrested at G2/M cell cycle checkpoint. Oct4 absence had a profound impact on cortical actin organization, with loss of microfilaments from cell membrane, increased puncta deposition in the cytoplasm and stress fiber formation. E-cadherin, {beta}-catenin and ZO1 were almost absent from cell-cell contacts while fibronectin deposition was markedly increased in ECM. Mapping of the transcriptional and chromatin profiles of Oct4-deficient cells revealed that Oct4 controls the levels of cytoskeletal, ECM and differentiation related genes, whereas epithelial identity is preserved through transcriptional and non-transcriptional mechanisms.

cell biology↗

bioRxiv2023

A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth

The validation of mathematical models of tumour growth is frequently hampered by the lack of sufficient experimental data, resulting in qualitative rather than quantitative studies. Recent approaches to this problem have attempted to extract information about tumour growth by integrating multiscale experimental measurements, such as longitudinal cell counts and gene expression data. In the present study, we investigated the performance of several mathematical models of tumour growth, including classical logistic, fractional and novel multiscale models, in terms of quantifying in-vitro tumour growth in the presence and absence of therapy. We further examined the effect of genes associated with changes in chemosensitivity in cell death rates. State-of-the-art Bayesian inference, likelihood maximisation and uncertainty quantification techniques allowed a thorough evaluation of model performance. The results suggest that the classical single-cell population model (SCPM) was the best fit for the untreated and low-dose treatment conditions, while the multiscale model with a cell death rate symmetric with the expression profile of OCT4 (SymSCPM) yielded the best fit for the high-dose treatment data. Further identifiability analysis showed that the multiscale model was both structurally and practically identifiable under the condition of known OCT4 expression profiles. Overall, the present study demonstrates that model performance can be improved by incorporating multiscale measurements of tumour growth.

systems biology↗

bioRxiv2023

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer.

The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in HPV-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4 driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate transcription by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis. TeaserE7 modulates Oct4 interactions and related characteristics in cervical cancer cells by altering the DNA methylome.

cancer biology↗

bioRxiv2021

A novel lineage-tracing mouse model for MmuPV1 infection enables in vivo studies in the absence of cytopathic effects

Human papillomaviruses (HPVs) are DNA viruses that ubiquitously infect humans and have been associated with hyperproliferative lesions. The recently discovered mouse specific papillomavirus, MmuPV1, provides the opportunity to study papillomavirus infections in vivo in the context of a common laboratory mouse model (Mus musculus). To date, a major challenge in the field has been the lack of tools to identify, observe and characterize individually the papillomavirus hosting cells and also trace the progeny of these cells over time. Here, we present the successful generation of an in vivo lineage-tracing model of MmuPV1-harboring cells and their progeny by means of genetic reporter activation. Following the validation of the system both in vitro and in vivo, we used it to provide a proof-of-concept of its utility. Using flow-cytometry analysis, we observed increased proliferation dynamics and decreased MHC-I cell surface expression in MmuPV1-treated tissues which could have implications in tissue regenerative capacity and ability to clear the virus. This model is a novel tool to study the biology of the MmuPV1 host-pathogen interactions.

microbiology↗