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Upcoming Seminars

Angela Gritti, - Head of Unit Gene Therapy, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy

When Apr 11, 2017
from 12:00 AM to 01:30 AM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Lisa Swanton, Ph.D. - "Quality control of transmembrane domains within the secretory pathway"

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
When Apr 12, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Short CV

Abstract
Cells are constantly threatened by the production of misfolded and damaged proteins, the accumulation of which can be catastrophic. Therefore, proteins that fail to fold correctly or become damaged must be efficiently identified and eliminated. This is achieved by quality control systems which detect specific features of misfolded proteins and target them for degradation by the proteasome or in lysosomes. Around 20% of the human proteome is made up of integral membrane proteins, which have one or more hydrophobic transmembrane domains that anchor the protein into the lipid bilayer. The biosynthesis of membrane proteins is a complex process and many human diseases are linked to the misfolding of membrane proteins. Therefore, there is great interest in understanding the quality control pathways that identify and remove misfolded membrane proteins in order to maintain cellular and organismal integrity. In contrast to the well-studied quality control systems that scrutinise folding of protein domains in the cytoplasm and endoplasmic reticulum lumen, little is known about the how folding and assembly of transmembrane domains within the lipid bilayer is monitored. In this talk, I will describe our recent work examining where and how non-native transmembrane domains are detected within mammalian cells. Our results point to the existence of multiple transmembrane domain-based quality control checkpoints, including a novel mechanism that detects and rapidly removes proteins containing non-native transmembrane domains from the plasma membrane. 

Mario Nicodemi, - "Mapping chromatin in 4D"

Dipartimento di Fisica "E. Pancini", Universita' di Napoli "Federico II", Napoli, Italy
When Apr 28, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Short CV

Abstract
Structural variants (SVs) contribute to a high degree of the variability of our genome and are a common cause of disease. Their effects are often difficult to predict, yet novel technologies, such as Hi-C or our recent GAM method [1], show that SVs can alter the genome 3D architecture inducing new contacts between enhancers and genes, leading to gene misexpression in congenital diseases.
In my general talk, I discuss first the current picture of chromosome spatial organization emerging from Hi-C and GAM data in mouse and human cells and tissues. We mapped chromatin contacts, in particular, during differentiation from proliferating mESCs, through neuronal precursors and terminally differentiated neurons [2]. We found that the genome is folded in a hierarchy of domains-within-domains, irrespective of cell types. The higher-order organization extends across genomic scales up to entire chromosomes and correlates with genetic, epigenetic and expression features. Specifically, architectural rearrangements observed during differentiation correlate with changes in transcriptional states, highlighting a functional role of the spatial organization far beyond simple packing efficiency.
Next, I discuss how architecture data and folding mechanisms can be understood genome-wide by new methods based on polymer physic (PRISMR) [3,4,5]. Using the EPHA4 locus as a model, I show that the effects of pathogenic structural variants can be predicted in-silico and compared to Hi-C/GAM data generated from mouse limb buds and patient-derived fibroblasts. PRISMR accurately predicts the SV-induced alterations of architecture and the specific ectopic contacts that produce extensive rewiring of enhancer-promoter regulatory interactions, causing disease by gene misexpression. It can predict interactions in-silico genome-wide thereby providing a tool for analyzing the disease causing potential of SVs and opening the way to novel diagnostic methods.

[1] R.A. Beagrie, A. Scialdone, M. Schueler, D.C.A. Kraemer, M. Chotalia, S.Q. Xie, M. Barbieri, I. de Santiago, L.-M. Lavitas, M.R. Branco, J. Fraser, J. Dostie, L. Game, N. Dillon, P.A.W. Edwards, M. Nicodemi*, A. Pombo*, Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM), a novel ligation-free approach. Nature, doi:10.1038/nature21411 (2017).   (* joint last authors)

[2] J. Fraser, C. Ferrai, A.M. Chiariello, M. Schueler, T. Rito, G. Laudanno, M. Barbieri, B.L. Moore, D.C.A. Kraemer, S. Aitken, S.Q. Xie, K. Morris, M. Itoh, H. Kawaji, I. Jaeger, Y. Hayashizaki, P. Carninci, A.R.R. Forrest, FANTOM, C.A. Semple, J. Dostie, A. Pombo, M. Nicodemi. Hierarchical folding of chromosomes is linked to transcriptional changes in cellular differentiation. Molecular System Biology 11, 852 (2015).  

[3] A.M. Chiariello, S. Bianco, C. Annunziatella, A. Esposito, M. Nicodemi, Polymer physics of chromosome large-scale 3D organisation, Nature Scientific Reports 6, 29775 (2016).

[4] M. Barbieri, S.Q. Xie, E. Torlai Triglia, A.M. Chiariello, S. Bianco, I. de Santiago, M.R. Branco, D. Rueda, M. Nicodemi*, A. Pombo*, Active and poised promoter states drive folding of the extended HoxB locus in mouse embryonic stem cells. Nature Struct. Mol. Bio., in press (2017).   (* joint last author)

[5] S. Bianco, D.G. Lupiáñez, A.M. Chiariello, C. Annunziatella, K. Kraft, R. Schöpflin, L. Wittler, G. Andrey, M. Vingron, A. Pombo, S. Mundlos, M. Nicodemi, Polymer physics predicts the effects of structural variants on chromatin architecture, submitted (2017)

Vincenzo Costanzo, M.D., Ph.D. - DNA metabolism laboratory, IFOM, Milan, Italy

When May 02, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Irene Bozzoni, M.Sc. - Dept. of Biology and Biotechnology "Charles Darwin" Sapienza - University of Rome, Rome, Italy

When May 09, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Angelo Lombardo, M.Sc. - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy

When May 30, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Amit Nathwani, M.D. - Department of Haematology, University College London Cancer Institute, London, UK

When Jun 06, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Ido Amit, Ph.D. - Immunology Department , Weizmann Institute of Science, Rehovot, Israel

When Jun 20, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Christian Behrends, M.Sc., Ph.D. - "Expanding the functions of autophagy regulators to the nucleus"

Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich (LMU), Munich, Germany
When Jun 27, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Short CV

Abstract
Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator.