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Diabetologia. 2016 Jul;59(7):1463-1473. doi: 10.1007/s00125-016-3945-0. Epub 2016 Apr 8.

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.

Author information

1
Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland. wojciech.fendler@umed.lodz.pl.
2
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 36/50 Sporna Str., 91-738, Lodz, Poland. wojciech.fendler@umed.lodz.pl.
3
Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
4
Studies in Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
5
Laboratory of Cell Signalling and Metabolic Disorders, Nencki Institute of Experimental Medicine, Polish Academy of Sciences, Warsaw, Poland.
6
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
7
Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
8
University Hospital, Krakow, Poland.
9
Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
10
Department of Paediatric Diabetology, Medical University of Silesia, Katowice, Poland.
11
Department of Paediatrics, Diabetology and Endocrinology, Medical University of Gdansk, Gdansk, Poland.

Abstract

AIMS/HYPOTHESIS:

We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β 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 HbA1c-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 HNF1α or HNF1β.

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 HNF1α- than in HNF1β-deficient HepG2 cells.

CONCLUSIONS/INTERPRETATION:

We have shown that expression of specific miRNAs depends on HNF1β function. The impact of HNF1β deficiency was evidenced at serum level, making HNF1β-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY.

KEYWORDS:

HNF; MODY; Monogenic diabetes; Transcription factors; microRNA

PMID:
27059371
PMCID:
PMC4901123
DOI:
10.1007/s00125-016-3945-0
[Indexed for MEDLINE]
Free PMC Article

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