Biology subjects

Vanzan, L.

Publications and source records attributed to Vanzan, L..

5 recordsLinked to original sources

bioRxiv2026

STAT transcription factors regulate host defences and vacuolar integrity during Mycobacterium marinum infection

Signal transducers and activators of transcription (STAT) are central regulators of cytokine-mediated immunity in metazoans, yet their ancestral functions prior to the emergence of interferon signalling remain poorly understood. Dictyostelium discoideum expresses four STAT-like factors that impact the intracellular fate of Mycobacterium marinum (Mm). Using dst knockout strains, we identify DstA and DstB as susceptibility factors, whereas DstC acts as a resistance factor, revealing a regulatory axis controlling the integrity of the Mm-containing vacuole (MCV). Despite the absence of canonical cytokine receptors and JAK kinases, DstA rapidly translocates to the nucleus in a damage-dependent manner, whereas DstB and DstC exhibit delayed cytosolic redistribution. DstA associates with VacA, a membrane microdomain component, regulates its transcription and accumulation at the MCV, while VacA acts as a cytoplasmic anchor that limits DstA nuclear translocation. Our findings establish STAT-like proteins as evolutionarily ancient regulators of vacuole integrity and host defence, providing new insights into the origins of STAT-mediated immune responses during mycobacterial infection.

microbiology↗

bioRxiv2026

The role of charge, hydrophobicity, and cooperativity in target search of SOX2 and ESRRB

Transcription factors (TFs) locate and bind specific DNA sequences within a crowded nuclear environment, yet how their biophysical properties and interactions influence their search remains unclear. Here, we modulate hydrophobicity and charge of the pluripotency TFs SOX2 and ESRRB, and combine single-molecule imaging with genomic analyses to dissect their target search dynamics. We show that increased hydrophobicity impairs specific binding while promoting confined intranuclear interactions, whereas additional negative charges decrease sampling of weak binding sites. While SOX2 retains effective target site recognition despite decreased search efficiency, impairment of ESRRB search results in a global loss of genome occupancy and redirection to SOX2-bound regions, indicating a strong reliance of ESRRB on TF-TF interactions for locating its binding sites. Single molecule imaging analysis of ESRRB search upon SOX2 depletion demonstrated that SOX2 reduces ESRRB search time by restricting its nuclear diffusion and facilitating stable DNA binding. Together, our findings highlight how TF biophysical features and cooperativity jointly shape the efficiency and specificity of target search in the nucleus.

molecular biology↗

bioRxiv2023

Orchestration of pluripotent stem cell genome reactivation during mitotic exit

The maintenance of cell identity faces many challenges during mitosis, as most DNA-binding proteins are evicted from DNA and transcription is virtually abolished. How cells maintain their identity through cell division and faithfully re-initiate gene expression during mitotic exit is unclear. Here, we developed a novel reporter system enabling cell cycle synchronization-free separation of pluripotent stem cells in temporal bins of < 30 minutes during mitotic exit. This allowed us to quantify genome-wide reactivation of transcription, sequential changes in chromatin accessibility, and re-binding of the pluripotency transcription factors OCT4, SOX2, and NANOG (OSN). We found that transcriptional activity progressively ramped up after mitosis and that OSN rapidly reoccupied the genome during the anaphase-telophase transition. We also demonstrate transcription factor-specific, dynamic relocation patterns and a hierarchical reorganization of the OSN binding landscape governed by OCT4 and SOX2. Our study sheds light on the dynamic orchestration of transcriptional reactivation after mitosis.

molecular biology↗

bioRxiv2020

High throughput screening identifies SOX2 as a Super Pioneer Factor that inhibits DNA methylation maintenance at its binding sites

Access of mammalian transcription factors (TFs) to regulatory regions, an essential event for transcription regulation, is hindered by chromatin compaction involving nucleosome wrapping, repressive histone modifications and DNA methylation. Moreover, methylation of TF binding sites (TBSs) affects TF binding affinity to these sites. Remarkably, a special class of TFs called pioneer transcription factors (PFs) can access nucleosomal DNA, leading to nucleosome remodelling and chromatin opening. However, whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Here, we set up a highly parallelized approach to investigate PF ability to bind methylated DNA and induce demethylation. Our results indicate that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs that have a strong pioneering activity; while most PFs do not induce changes in DNA methylation at their binding sites, we identified PFs that can protect DNA from methylation and PFs that can induce DNA demethylation at methylated binding sites. We called the latter "super pioneer transcription factors" (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Importantly, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation by inhibition of the maintenance methyltransferase DNMT1 during replication. This important finding suggests a novel mechanism allowing TFs to interfere with the epigenetic memory during DNA replication.

genetics↗

bioRxiv2019

Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Expanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy (DM1) and Huntingtons disease (HD). Upon expansion, CAG/CTG repeat loci acquire heterochromatic characteristics. This observation raises the hypothesis that repeat expansion provokes changes to higher order chromatin folding and thereby affects both gene expression in cis and the genetic instability of the repeat tract. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. Surprisingly, chromatin contacts remain unchanged upon repeat expansion at both loci. This was true for loci with different DNA methylation levels and CTCF binding. Repeat sizes ranging from 15 to 1,700 displayed strikingly similar chromatin interaction profiles. Our findings argue that extensive changes in heterochromatic properties are not enough to alter chromatin folding at expanded CAG/CTG repeat loci. Moreover, the ectopic insertion of an expanded repeat tract did not change three-dimensional chromatin contacts. We conclude that expanded CAG/CTG repeats have little to no effect on chromatin conformation.

neuroscience↗