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Diabetologia. 2016 Jul;59(7):1463-73. 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

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