CIBIO - Ph.D. Colloquia 2018

Seminar series

May-December 2018
Versione stampabile

 

 

This is a series of 6 seminars given by top experts in different fields covering almost all the area of the PhD program. Each colloquium is a friendly forum where students can learn how to communicate and critically evaluate science. Additionally, it is an opportunity to discuss ongoing research in an informal atmosphere and obtain valuable feedbacks from the experts.
PhD Colloquia bring together young scientists, senior scientists and students in a colloquial setting, encouraging interactions and exchanges of ideas.

Next Seminar

Tuesday, October 30th

Post transcriptional regulations are crucial for the physiological functions of mammalian cells. The cell fate of any mRNA is controlled by its association to proteins to form the so-called ribonucleoproteins (RNPs) that drive the spatiotemporal control of protein synthesis. mRNA stability and translation are often coupled but the molecular mechanisms are still poorly understood. Communication between eIF4E bound to the 5’end of the mRNA and the PABPs bound to the polyA tail at the 3’end appears to be crucial for both stability and translational control. In this context, it was particularly interesting to identify Angel1, a member of the CCR4 deadenylase family, as a new partner of eIF4E.  
Cell fractionation experiments revealed that Angel1 is not co-distributed with 4E-BP1, the most extensively studied eIF4E regulator that negatively regulates translation. Immunofluorescence experiments showed that Angel1 displays a specific perinuclear localization, co-localizing with eIF4E and overlapping partially with Endoplasmic Reticulum (ER) and Golgi apparatus staining. We thus hypothesize that Angel1 is a specific regulator of mRNAs localized to the ER. 
We explored the capacity of Angel1 to regulate specific mRNAs by Ribosome Profiling. We designed a bio-informatic pipeline to integrate mRNA abundance and translation profiles following Angel1 knock-down. We found that Angel1 depletion affect translation of a subset of mRNAs, the majority of which have been previously described to localize to the ER. 
I will discuss how these results are integrated in the complex pattern of regulation orchestrated at a post-transcriptional level.

Thursday, October 25th

Widespread transcriptional activity across the mammalian genome results in the production of many functional noncoding RNAs (ncRNAs) involved in multiple biological processes. They are critical for the formation of chromatin architecture that is shaped by epigenetic marks such as DNA methylation, histone modifications, nucleosome positioning and the incorporation of histone variants into nucleosomes. The cumulative effect of these epigenetic marks is to provide another layer of control for cell-type specific gene expression. Indeed, aberrant epigenetic signatures are the hallmark of deleterious conditions such as cancers and other genetic diseases. Despite their well-documented associative roles in gene regulation, the mechanisms guiding the establishment of such marks have yet to be defined.
We have previously discovered a class of RNAs with the ability to regulate DNA methylation: the DNA Methyltransferase 1 (DNMT1)-interacting RNAs or DiRs. DiRs inhibit DNMT1 enzymatic activity and protect DiR-expressing loci from DNA methylation and silencing. We demonstrated that the RNA-DNMT1 association is widespread and negatively correlates with DNA methylation pro les. We have now identified another class of RNAs that are induced in the early S phase termed SPEARs (S Phase EArly RNAs), which set the stage for the acetylation and deposition of the acetylated form of histone H2A.Z. These findings indicate a novel mechanistic role for transcriptional activity in triggering epigenetic changes and suggest the potential application of RNA molecules as gene-selective tool to correct aberrant epigenetic changes.

Thursday, September 27th - Room B105 at 5:00pm

  • Frederic SaudouGIN/INSERM, Grenoble, France
    Huntingtin: Linking Fast Axonal Transport, Energy Supply and Neurotrophin Signaling to Neutodegeneration  

Huntington’s disease is caused by the abnormal polyglutamine expansion in the N-ter part of huntingtin (HTT), a large protein of 350kDa. Over the past years, we proposed that HTT acts a scaffold for the molecular motors and through this function, regulates the efficiency and directionality of vesicular transport along microtubules in neurons. This function is conserved in Drosophila. In particular, HTT controls the microtubule-based fast axonal transport (FAT) of neurotrophic factors such as BDNF. HTT function in transport is modulated by direct phosphorylation/dephosphorylation via specific signaling pathways. Importantly, polyQ expansion in HTT alters this function, leading to a decrease in neurotrophic support and death of striatal neurons. The defect in transport might not be restricted to axons but could also involve defects in the retrograde transport of TrkB in striatal dendrites.
In addition to the role of HTT in scaffolding the molecular motors both in cortical and striatal neurons, we found that HTT scaffolds GAPDH on vesicles and that vesicular GAPDH is necessary to propel vesicles in GAPDH deficient neurons. Here we will extend these findings and discuss how HTT by specifically localizing the glycolytic machinery on vesicles may supply constant energy for the transport of vesicles over long distances in axons.
We will also discuss how this machinery is altered in disease situation using new approaches that allow the study of defective networks in vitro through the development of microfluidic systems compatible with high-resolution videomicroscopy and the use of biosensors to reconstitute and identify each component of the corticostriatal network.

Friday, June 22nd

  • Anna ObenaufIMP Vienna Biocenter, Vienna, Austria
    The tumor microenvironment in therapy response and resistance: challenges and opportunity

    The identification of molecular drivers in cancer has paved the way for targeted therapy. However, incomplete responses and relapse on therapy remain the biggest problem for improving patient survival. Evidence suggests that a tumor consists of a majority of cells that are sensitive to targeted therapy while few cells that are intrinsically resistant or poised to quickly adapt to drug treatment already pre-exist within this heterogeneous tumor population. Although a multitude of resistance mechanisms have been described, it was largely unknown how resistant cells behave in a heterogeneous tumor during treatment and whether the microenvironment of a regressing tumor could influence disease relapse.

    We found that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) stimulates the outgrowth, dissemination, and metastasis of drug-resistant cancer cell clones in the heterogenous tumors and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones but is susceptible to combination therapy. Finally, I will discuss how a better understanding of the therapy-induced alterations in the tumor microenvironment could open up new possibilities for potent therapeutic combinations, including combinations with immunotherapies.

Thursday, May 3rd

  • Tord Berdlungh, DDS, PhD. Dept. of Periodontology, University of Gothenburg, Sweden
    Peri-implantitis and periodontitis - disease models to study host-parasite interactions

    The identification of molecular drivers in cancer has paved the way for targeted therapy. However, incomplete responses and relapse on therapy remain the biggest problem for improving patient survival. Evidence suggests that a tumor consists of a majority of cells that are sensitive to targeted therapy while few cells that are intrinsically resistant or poised to quickly adapt to drug treatment already pre-exist within this heterogeneous tumor population. Although a multitude of resistance mechanisms have been described, it was largely unknown how resistant cells behave in a heterogeneous tumor during treatment and whether the microenvironment of a regressing tumor could influence disease relapse.

    We found that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) stimulates the outgrowth, dissemination, and metastasis of drug-resistant cancer cell clones in the heterogenous tumors and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones but is susceptible to combination therapy. Finally, I will discuss how a better understanding of the therapy-induced alterations in the tumor microenvironment could open up new possibilities for potent therapeutic combinations, including combinations with immunotherapies. 

 

 

Wednesday, December 12th

 

Free entrance. Organized by PhD students enrolled in cycle 31st.
Info: phd.bioscie [at] unitn.it

Sponsored by:

 

                

       Tema Ricerca          

DBA       Vinci Biochem   

 

Thanks to: