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The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity article


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dc.creator Mellado Gil, José Manuel es
dc.creator Fuente Martín, Esther es
dc.creator Lorenzo Ovejero, Petra Isabel es
dc.creator Cobo Vuilleumier, Nadia es
dc.creator López Noriega, Livia es
dc.creator Martín Montalvo, Alejandro es
dc.creator Gracia Herrera Gómez, Irene de es
dc.creator Ceballos Chávez, María es
dc.creator Romero Zerbo, Silvana Y. es
dc.creator Hmadcha, Abdelkrim es
dc.creator Soria Escoms, Bernat es
dc.creator Bermúdez Silva, Francisco Javier es
dc.creator Reyes, José C. es
dc.creator Gauthier, Benoit R. es 2018-10-17T15:10:46Z 2018-10-17T15:10:46Z 2018
dc.identifier.citation Mellado Gil, J.M., Fuente Martín, E., Lorenzo Ovejero, P.I., Cobo Vuilleumier, N., López Noriega, L., Martín Montalvo, A.,...,Gauthier, B.R. (2018). The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity article. Cell Death and Disease, 9 (3), 279.
dc.identifier.issn 2041-4889 es
dc.description.abstract HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3′ UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function. es
dc.description.sponsorship Junta de Andalucía PI-0727-2010, PI-0085-2013, PI-0006-2016, PI-0574-2012, P10.CTS.6359, P09-CTS-5445, RH-0070-2013, C-0070-2012 es
dc.description.sponsorship Ministerio de Economía y Competitividad PI10/00871, PI13/00593, BFU2014-5343-P, RD12/0019/0028, IJCI-2015-26238 es
dc.format application/pdf es
dc.language.iso spa es
dc.publisher Springer Nature [academic journals on es
dc.relation.ispartof Cell Death and Disease, 9 (3), 279.
dc.rights Attribution-NonCommercial-NoDerivatives 4.0 Internacional *
dc.rights.uri *
dc.title The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity article es
dc.type info:eu-repo/semantics/article es
dc.type.version info:eu-repo/semantics/publishedVersion es
dc.rights.accessrights info:eu-repo/semantics/openAccess es
dc.relation.projectID PI-0727-2010 es
dc.relation.projectID PI-0085-2013 es
dc.relation.projectID PI-0006-2016 es
dc.relation.projectID PI-0574-2012 es
dc.relation.projectID P10.CTS.6359 es
dc.relation.projectID P09-CTS-5445 es
dc.relation.projectID RH-0070-2013 es
dc.relation.projectID C-0070-2012 es
dc.relation.projectID PI10/00871 es
dc.relation.projectID PI13/00593 es
dc.relation.projectID BFU2014-5343-P es
dc.relation.projectID RD12/0019/0028 es
dc.relation.projectID IJCI-2015-26238 es
dc.relation.publisherversion es
dc.identifier.doi 10.1038/s41419-018-0272-z es
idus.format.extent 15 p. es
dc.journaltitle Cell Death and Disease es
dc.publication.volumen 9 es
dc.publication.issue 3 es
dc.publication.initialPage 279 es
dc.contributor.funder Junta de Andalucía
dc.contributor.funder Ministerio de Economía y Competitividad (MINECO). España
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