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Mario Nicodemi, Ph.D. - "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"
Contact Name
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)

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