Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Græcia, viale Europa (Loc. Germaneto), Catanzaro 88100, Italy.
Nat Commun. 2010 Jul 27;1:40. doi: 10.1038/ncomms1040.
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.
已加工的假基因是通过 mRNA 反转录过程产生的正常基因的非功能副本。人类基因组包含数千个假基因；然而，关于它们的生物学作用的知识是有限的。此前，我们证明了高迁移率族蛋白 A1（HMGA1）蛋白调节胰岛素受体（INSR）基因，并且两名糖尿病患者表现出 HMGA1 mRNA 的明显不稳定性。在本文中，我们报告说，HMGA1 假基因 HMGA1-p 的 RNA 表达增强触发了 HMGA1 mRNA 的这种不稳定性。在患者细胞中靶向敲低 HMGA1-p mRNA 会导致 HMGA1 mRNA 稳定性和表达水平的反向增加，同时细胞表面 INSR 表达和胰岛素结合得到平行纠正。这些数据为人类中表达的假基因的调节作用提供了证据，并在假基因 HMGA1-p 表达与 2 型糖尿病之间建立了一种新的机制联系。
