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; Antonio Brunetti

doi:10.1038/ncomms1040

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, Antonio Brunetti

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Communications
Volume	1
Issue number	4
DOIs	https://doi.org/10.1038/ncomms1040
Publication status	Published - 2010

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Chemistry(all)
Physics and Astronomy(all)

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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. / Chiefari, Eusebio; Iiritano, Stefania; Paonessa, Francesco; Le Pera, Ilaria; Arcidiacono, Biagio; Filocamo, Mirella; Foti, Daniela; Liebhaber, Stephen A.; Brunetti, Antonio.

In: Nature Communications, Vol. 1, No. 4, 2010.

Research output: Contribution to journal › Article › peer-review

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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.",

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AU - Iiritano, Stefania

AU - Paonessa, Francesco

AU - Le Pera, Ilaria

AU - Arcidiacono, Biagio

AU - Filocamo, Mirella

AU - Foti, Daniela

AU - Liebhaber, Stephen A.

AU - Brunetti, Antonio

PY - 2010

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AB - 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.

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

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