Differential regulation of serum microRNA expression by HNF1 beta and HNF1 alpha transcription factors

作者：Fendler Wojciech^*; Madzio Joanna; Kozinski Kamil; Patel Kashyap; Janikiewicz Justyna; Szopa Magdalena; Tracz Adam; Borowiec Maciej; Jarosz Chobot Przemyslawa; Mysliwiec Malgorzata; Szadkowska Agnieszka; Hattersley Andrew T; Ellard Sian; Malecki Maciej T; Dobrzyn Agnieszka; Mlynarski Wojciech

来源：Diabetologia, 2016, 59(7): 1463-1473.

DOI：10.1007/s00125-016-3945-0

• HNF
• microRNA
• MODY
• Monogenic diabetes
• Transcription factors

Aims/hypothesis We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1 beta transcription factor, and investigate whether its effect manifests in serum.
Methods The Polish cohort (N = 60) consisted of 11 patients with HNF1B-MODY, 17 with HNF1A-MODY, 13 with GCK-MODY, an HbA(1c)-matched type 1 diabetic group (n = 9) and ten healthy controls. Replication was performed in 61 clinically-matched British patients mirroring the groups in the Polish cohort. The Polish cohort underwent miRNA serum level profiling with quantitative real-time PCR (qPCR) arrays to identify differentially expressed miRNAs. Validation was performed using qPCR. To determine whether serum content reflects alterations at a cellular level, we quantified miRNA levels in a human hepatocyte cell line (HepG2) with small interfering RNA knockdowns of HNF1 alpha or HNF1 beta.
Results Significant differences (adjusted p < 0.05) were noted for 11 miRNAs. Five of them differed between HNF1A-MODY and HNF1B-MODY, and, amongst those, four (miR-24, miR-27b, miR-223 and miR-199a) showed HNF1B-MODY-specific expression levels in the replication group. In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups. Areas under the receiver operating characteristic curves ranged from 0.79 to 0.86, with sensitivity and specificity reaching 91.7% (miR-24) and 82.1% (miR-199a), respectively. The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1 alpha- than in HNF1 beta-deficient HepG2 cells.
Conclusions/interpretation We have shown that expression of specific miRNAs depends on HNF1 beta function. The impact of HNF1 beta deficiency was evidenced at serum level, making HNF1 beta-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY.

• 出版日期2016-7