Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes.
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.
Chiefari
Eusebio
E
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Græcia, viale Europa (Loc. Germaneto), Catanzaro 88100, Italy.
Iiritano
Stefania
S
Paonessa
Francesco
F
Le Pera
Ilaria
I
Arcidiacono
Biagio
B
Filocamo
Mirella
M
Foti
Daniela
D
Liebhaber
Stephen A
SA
Brunetti
Antonio
A
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D020868:Gene Silencing; D057809:HEK293 Cells; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011544:Pseudogenes / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D015703:Antigens, CD; D024003:HMGA Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin