Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes

Eusebio Chiefari, Stefania Iiritano, Francesco Paonessa, Ilaria Le Pera, Biagio Arcidiacono, Mirella Filocamo, Daniela Foti, Stephen A. Liebhaber and Antonio Brunetti ()
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Eusebio Chiefari: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Stefania Iiritano: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Francesco Paonessa: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Ilaria Le Pera: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Biagio Arcidiacono: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Mirella Filocamo: Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5
Daniela Foti: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
Stephen A. Liebhaber: University of Pennsylvania School of Medicine, 415 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.
Antonio Brunetti: Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)

Nature Communications, 2010, vol. 1, issue 1, 1-7

Abstract: Abstract Processed pseudogenes are non-functional copies of normal genes that arise by a process of mRNA retrotransposition. The human genome contains thousands of pseudogenes; however, knowledge regarding their biological role is limited. Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. In this paper we report that this destabilization of HMGA1 mRNA is triggered by enhanced expression of RNA from an HMGA1 pseudogene, HMGA1-p. Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. These data provide evidence for a regulatory role of an expressed pseudogene in humans and establishes a novel mechanistic linkage between pseudogene HMGA1-p expression and type 2 diabetes mellitus.

Date: 2010
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DOI: 10.1038/ncomms1040

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