Biology subjects

Promponas, V.

Publications and source records attributed to Promponas, V..

3 recordsLinked to original sources

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↗

bioRxiv2023

Deformed wings is an Atg8a-interacting protein that negatively regulates autophagy

LC3 (microtubule-associated protein 1 light chain 3, called Atg8 in yeast and Drosophila), is one of the most well-studied autophagy-related proteins. LC3 controls selectivity of autophagic degradation by interacting with LIR (LC3-interacting region) motifs also known as AIM (Atg8-interacting motifs) on selective autophagy receptors that carry cargo for degradation. Non-degradative roles of LIR motif-dependent interactions of LC3 are poorly understood. Here, we used yeast-two hybrid screening and Alpha Fold structural predictions, and we identified transcription factor Dwg (Deformed wings) as an Atg8a-interacting protein in Drosophila. Dwg-Atg8a interaction is LIR-motif dependent. We further show that Dwg is a negative regulator of autophagy. Our results provide novel insights on non-degradative roles of LIR motif dependent interactions of Atg8a and the transcriptional regulation of autophagy in Drosophila.

cell biology↗

bioRxiv2019

Pseudomonas aeruginosa core metabolism exerts a widespread growth-independent control on virulence

Bacterial virulence may rely on secondary metabolism, but core metabolism genes are assumed to be necessary primarily for bacterial growth. To assess this assumption, we correlated the genome, the transcriptome and the pathogenicity of 30 fully sequenced Pseudomonas strains using two Drosophila and one mouse infection assay. In accordance with previous studies gene presence-absence does not explain differences in virulence among P. aeruginosa strains, but merely between P. aeruginosa and other Pseudomonas species. Similarly, classical gene expression analysis of highly vs. lowly pathogenic P. aeruginosa strains identifies many virulence factors, and only a few metabolism genes related to virulence. Nevertheless, assessing the virulence of 553 core metabolic and 95 random non-metabolic gene mutants of P. aeruginosa PA14, we found 16.5% of the core metabolic and 8.5% of the non-metabolic genes to be necessary for full virulence. Strikingly, 11.8% of the core metabolism genes exhibit defects in virulence that cannot be attributed to auxotrophy. The compromised in virulence metabolic gene mutants were mapped in multiple pathways and exhibited further defects in acute virulence phenotypes and in a mouse lung infection model. Functional transcriptomics re-analysis of core metabolism at the pathway level, reveals amino-acid, succinate, citramalate, and chorismate biosynthesis and beta-oxidation as important for full virulence and expression of these pathways indicative of virulence in various strains. Thus, P. aeruginosa virulence variation, which to this point remains unpredictably combinatorial at the gene level, can be dissected at the pathway level via combinatorial trancriptome and functional core metabolism analysis.

microbiology↗