Biology subjects

Sole, C.

Publications and source records attributed to Sole, C..

5 recordsLinked to original sources

bioRxiv2025

POZ Domain Transcription Factor Kaiso is a Downstream Effector of STAT1 for Multiple Myeloma Cell Survival and is also essential for Anoikis Resistance of Metastatic Solid Tumors

Role of the transcription factor STAT1 in cancer cell survival has remained unclear. Here we document an oncogenic role for STAT1 in Multiple Myeloma (MM), wherein STAT1 regulates Kaiso expression, represses bmf and is essential for MM cell survival. Moreover, STAT1 is constitutively phosphorylated in MM cell lines and patient derived primary MM cells and STAT1-depletion resulted in reduced Kaiso levels. Importantly, expression of exogenous Kaiso rescued STAT1-depleted MM cells from apoptosis by reversing elevated BMF levels. Further, several MM cell lines harboring diverse oncogenic mutations rely on Kaiso for their survival revealing an oncogenic addiction to Kaiso in MM. Mechanistically, Kaiso interacts with and recruits HDAC1 to pro-apoptotic gene bmf promoter to maintain repressive state. In line with this, depletion of Kaiso or HDAC1 results in elevated BMF levels and apoptosis of MM cells. Kaiso is abundantly expressed in several MM cell lines and patient derived primary MM cells. Interestingly, Kaiso interacting partner p120-catenin levels are very low/undetectable in MM indicating that Kaiso function in MM is p120-independent. While previous reports suggested anoikis promoting role for Kaiso in breast cancer, we show here that bmf repression by Kaiso is central to anoikis-resistance of metastatic solid tumors. Collectively, our data indicate that Kaiso is a downstream effector for STAT1 in MM cell survival and that Kaiso mediated bmf repression is central to MM cell survival and anoikis resistance of metastatic solid tumors. Targetting Kaiso-mediated bmf repression would enable us to develop common drug for MM and metastasis of solid tumors.

cancer biology↗

bioRxiv2024

Perturbation-driven transcriptional heterogeneity impacts cell fitness

Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability1-3. Indeed, even isogenic cell populations vary in quantifiable phenotypes. Here we generated a high-resolution single-cell yeast transcriptome atlas using genotype and clone RNA barcoded deletions to profile 3500 mutants under control and stress conditions in a genome-scale genetic and environmental perturbation screen. We uncovered a myriad of cell states within a population with specific transcriptional architectures that are both intrinsically and extrinsically regulated, thereby suggesting a continuum of cell states. Cell state occupancy and transition can be genetically modulated with specific mutants that act as state attractors, resulting in differential fitness. By exploiting the power of intra-genetic variability, we identified regulators of transcriptional heterogeneity that are functionally diverse and influenced by the environment. One-Sentence SummaryThe yeast single cell-transcriptome atlas based on RNA-traceable genetic perturbations served to map cellular states and define their underlying genetic basis.

genetics↗

bioRxiv2023

Somatic chromosome pairing has a determinant impact on 3D 1 chromatin organization

In the nucleus, chromatin is intricately structured into multiple layers of 3D organization important for genome activity. How distinct layers influence each other is not well understood. In particular, the contribution of chromosome pairing to 3D chromatin organization has been largely neglected. Here, we address this question in Drosophila, an organism that shows robust chromosome pairing in interphasic somatic cells. The extent of chromosome pairing depends on the balance between pairing and anti-pairing factors, with the anti-pairing activity of the CAP-H2 condensin II subunit being the best documented. Here, we identify the zinc-finger protein Z4 as a strong anti-pairer that interacts with and mediates the chromatin binding of CAP-H2. We also report that hyperosmotic cellular stress induces fast and reversible chromosome unpairing that depends on Z4/CAP-H2. And, most important, by combining Z4 depletion and osmostress, we show that chromosome pairing reinforces intrachromosomal 3D interactions. On the one hand, pairing facilitates RNAPII occupancy that correlates with enhanced intragenic gene-loop interactions. In addition, acting at a distance, pairing reinforces chromatin-loop interactions mediated by Polycomb (Pc). In contrast, chromosome pairing does not affect which genomic intervals segregate to active (A) and inactive (B) compartments, with only minimal effects on the strength of A-A compartmental interactions. Altogether, our results unveil the intimate interplay between inter-chromosomal and intra-chromosomal 3D interactions, unraveling the interwoven relationship between different layers of chromatin organization and the essential contribution of chromosome pairing.

genomics↗

bioRxiv2022

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

BackgroundEpigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. MethodsFunctional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. ResultsNeuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. ConclusionsWe report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.

cancer biology↗

bioRxiv2017

Timing of gene expression in a cell-fate decision system

During development, morphogens provide extracellular cues allowing cells to select a specific fate by inducing complex transcriptional programs. The mating pathway in budding yeast offers simplified settings to understand this process. Pheromone secreted by the mating partner triggers the activity of a MAPK pathway, which results in the expression of hundreds of genes. Using a dynamic expression reporter, we quantified the kinetics of gene expression in single cells upon exogenous pheromone stimulation and in the physiological context of mating. In both conditions, we observed striking differences in the timing of induction of mating-responsive promoters. Biochemical analyses and generation of synthetic promoter variants demonstrated how the interplay between transcription factor binding and nucleosomes contribute to determine the kinetics of transcription in a simplified cell-fate decision system.\n\nOne Sentence SummaryQuantitative and dynamic single cell measurements in the yeast mating pathway uncover a complex temporal orchestration of gene expression events.

systems biology↗