Project description:Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-Flouororuacil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-b. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-b treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-b, with the aim of avoiding resistance development and relapse in breast cancer.
Project description:Deciphering gene regulatory networks (GRNs) is a key for understanding gene expression regulations in living systems. Here, we describe the investigation of the ABSCISIC ACID INSENSITIVE 3 (ABI3) plant transcription factor GRN vicinity by a technique called Network Walking. The method involves transient transformation of protoplasts and inducible nuclear re-localization of transcription factors along with transcriptomic analysis. This genome-wide approach allowed the de novo recovery of i) direct and indirect ABI3 target genes, ii) cis-binding site preference, and iii) biological processes regulated by this canonical abscisic acid response factor. This work improves our knowledge of ABI3 action by inferring network motifs (such as Feed Forwar Loops) under its influence. The novel high-throughput-oriented technique will help accelerate GRN systems investigations in plants, as well as in other organisms. This work studies ABI3 direct and indirect targets by a technique named Network Walking. Root/protoplasts were treated with or without dexamethasone (DEX) and cycloheximide (CHX). 3 reps each.
Project description:The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict viral spread, whereas excessive ISG activation can result in IFN-related pathologies. Although both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that several ISGs regulate aspects of the IFN response themselves. In this study, we performed a CRISPR activation screen to identify previously unknown regulators of the type I IFN response. We identified the strongly induced ISG encoding ETS variant transcription factor 7 (ETV7) as a negative regulator of the type I IFN response. However, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of antiviral ISGs that were particularly important for IFN-mediated control of influenza viruses. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a potential therapeutic target to increase innate antiviral responses and enhance IFN-based antiviral therapies.
Project description:This is the first study deciphering the global regulatory network that drives human somatic cells during epigenetic rewiring towards the pluripotent state.
Project description:This is the first study deciphering the global regulatory network that drives human somatic cells during epigenetic rewiring towards the pluripotent state.