Abstract
Aims- Epidermal growth factor receptor (EGFR) signaling pathway is suggested to play a role in β-cell growth and islet development, and ERBB3 gene is an important member of this pathway. The genetic and regulatory architecture of the ERBB3 locus is not well explained with respect to type 1 diabetes. The aim of our study was to explore the role of ERBB3 locus in type 1 diabetes.
Methods- We genotyped 984 children with type 1 diabetes and examined if genetic variation of ERBB3 (rs2292239) affects residual β-cell function. Furthermore, we systematically explored the regulatory architecture of the ERBB3 locus, examined the expression of ERBB3 and its potential regulators in human islets and investigated the effect of ERBB3 knockdown on apoptosis in INS-1E cells.
Results- rs2292239 strongly correlated with residual β-cell function and metabolic control in children with type 1 diabetes. We identified evolutionary conserved long non-coding RNAs (lncRNAs) expressed in tissue-specific manner, multiple CTCF transcription factor binding sites and cis-eQTL signals, suggesting their putative regulatory roles in modulating ERBB3 expression. Additionally, we found that ERBB3, CTCF, and antisense lncRNA NONHSAG011351 are expressed in human islets and that ERBB3 is down-regulated by pro-inflammatory cytokines. Importantly, knockdown of ERBB3 in insulin producing INS-1E cells decreased the expression of CTCF and diminished basal and cytokine-induced apoptosis as shown by reduced Caspase-3 activation.
Methods- We genotyped 984 children with type 1 diabetes and examined if genetic variation of ERBB3 (rs2292239) affects residual β-cell function. Furthermore, we systematically explored the regulatory architecture of the ERBB3 locus, examined the expression of ERBB3 and its potential regulators in human islets and investigated the effect of ERBB3 knockdown on apoptosis in INS-1E cells.
Results- rs2292239 strongly correlated with residual β-cell function and metabolic control in children with type 1 diabetes. We identified evolutionary conserved long non-coding RNAs (lncRNAs) expressed in tissue-specific manner, multiple CTCF transcription factor binding sites and cis-eQTL signals, suggesting their putative regulatory roles in modulating ERBB3 expression. Additionally, we found that ERBB3, CTCF, and antisense lncRNA NONHSAG011351 are expressed in human islets and that ERBB3 is down-regulated by pro-inflammatory cytokines. Importantly, knockdown of ERBB3 in insulin producing INS-1E cells decreased the expression of CTCF and diminished basal and cytokine-induced apoptosis as shown by reduced Caspase-3 activation.
| Originalsprog | Engelsk |
|---|---|
| Publikationsdato | 2015 |
| Status | Udgivet - 2015 |
| Begivenhed | Annual Meeting of American Society of Human Genetics (ASHG) 2015: ASHG 2015 - Baltimore, USA Varighed: 6 okt. 2015 → 10 okt. 2015 http://www.ashg.org/2015meeting/ |
Konference
| Konference | Annual Meeting of American Society of Human Genetics (ASHG) 2015 |
|---|---|
| Land/Område | USA |
| By | Baltimore |
| Periode | 06/10/2015 → 10/10/2015 |
| Internetadresse |