BiMe

Genetic mechanisms underlying diabetes: insights from the noncoding genome

Datum
28.11.2019
Zeit
16:00 - 17:00
Sprecher
Prof. Jorge Ferrer
Zugehörigkeit
Centre for Genomic Regulation Barcelona, Regulatory genomics and diabetes lab, Genome Regulation Center-CRG and CIBERDEM
Serie
CMCB Life Sciences Seminar
Sprache
en
Hauptthema
Biologie
Andere Themen
Biologie, Medizin
Host
Dr. Anthony Gavalas (CRTD/PLID)
Beschreibung
Abstract: Most genetic mechanisms that are currently known to underlie developmental processes and human diseases have been discovered by analyzing a very small fraction of the genome that encodes for protein-coding sequences. Recent studies have revealed that large portions of the noncoding genome contain functional regulatory elements and noncoding transcripts. It is thus reasonable to presume that understanding the function of such elements can shed new light into developmental and cellular mechanisms, and uncover new causes of human disease.
Recent work has shown that common DNA variants in human pancreatic islet enhancers contribute to the risk of developing common polygenic forms of type 2 diabetes. Many of these diabetes risk variants are located in islet enhancer hubs that typically control multiple cell-specific target genes. The current challenge lies in using this information to dissect the mechanisms through which these regulatory variants impact pancreatic islets and polygenic diabetes. This effort could be assisted by the analysis of rare highly penetrant natural or artificial mutations, which can be used to provide insights into how noncoding DNA variants contribute to disease mechanisms.
Rare recessive mutations in an enhancer near PTF1A have been shown to cause neonatal diabetes associated with severe pancreas hypoplasia. I will discuss how modeling mutations in this enhancer provide unsuspected insights into the developmental and molecular mechanisms that underpin this regulatory defect.
Defects in long noncoding RNAs (lncRNAs) provide another potential mechanism of disease. Inhibition of several lncRNAs can impact gene expression and insulin secretion in cellular assays, but their physiological and disease relevance remains largely unexplored. I will discuss a genetic model that shows how disruption of a lncRNA can lead to severe pancreatic beta cell dysfunction and diabetes. Publications:* Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetesIrene Miguel-Escalada, Silvia Bonàs-Guarch, Inês Cebola, Joan Ponsa-Cobas, Julen Mendieta-Esteban, Delphine M.Y. Rolando, Biola M. Javierre, Goutham Atla, Irene Farabella, Claire C. Morgan, Javier García-Hurtado, Anthony Beucher, Ignasi Morán, Lorenzo Pasquali, Mireia Ramos, Emil V.R. Appel, Allan Linneberg, Anette P. Gjesing, Daniel R. Witte, Oluf Pedersen, Niels Garup, Philippe Ravassard, David Torrents, Josep Maria Mercader, Lorenzo Piemonti, Thierry Berney, Eelco J.P. de Koning, Julie Kerr-Conte, François Pattou, Iryna O. Fedko, Inga Prokopenko, Torben Hansen, Marc A. Marti-Renom, Peter Fraser, Ferrer JBiorxiv doi: https://doi.org/10.1101/400291. * Human pancreatic β cell lncRNAs control cell-specific regulatory networks.Akerman I, Tu Z, Beucher A, Rolando D, Sauty-Colace C, Benazra M, Nakic N, Yang J, Wang H, Pasquali L, Moran I, Garcia-Hurtado J, Castro N, Gonzalez-Franco R, Stewart A, Bonner C, Piemonti L, Berney T, Groop L, Kerr-Conte J, Pattou F, Argmann C, Schadt E, Ravassard P, Ferrer J.Cell Metab. 2017 February 7;25, 1–12. doi: 10.1016/j.cmet.2016.11.016. * Pasquali L*, Gaulton KJ*, Rodriques-Segul SA*, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Moran I, Gomez-Marin C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, Garcia-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Gomez-Skarmeta JL, Mueller F, McCarthy MI, Ferrer J. Pancreatic islet enhancer cluster enriched in type 2 diabetes risk-associatedvariants.Nature Genetics 2014 Feb 46 (2): 136-43, * Equal contribution * Pancreatic exocrine duct cells give rise to insulin-producing ß-cells duringembryogenesis but not after birth.Solar M*, Cardalda C*, Houbracken I*, Martín M, Maestro M, De Medts N, Xu X, Grau V, Heimberg H, Bouwens L, Ferrer J.Dev Cell, 2009 Dec; 17 ( 6): 849-860. *equal contribution PMID: 20059954
Links

Letztmalig verändert: 19.11.2019, 00:08:06

Veranstaltungsort

DFG Center for Regenerative Therapies Dresden (CRTD, ground floor, auditorium left)Fetscherstraße10501307Dresden
Telefon
+49 (0)351 458 82064
Fax
+49 (0)351 458 82059
E-Mail
CRTD
Homepage
http://www.crt-dresden.de

Veranstalter

Center for Regenerative Therapies DresdenFetscherstraße 10501307Dresden
Telefon
+49 (0)351 458 82064
Fax
+49 (0)351 458 82059
E-Mail
TUD CRTD
Homepage
http://www.crt-dresden.de
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