title: Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.
abstract: We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland. wojciech.fendler@umed.lodz.pl.|Department of Biostatistics and Translational Medicine, Medical University of Lodz, 36/50 Sporna Str., 91-738, Lodz, Poland. wojciech.fendler@umed.lodz.pl.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Fendler
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.|Studies in Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Madzio
authors.affiliation: Laboratory of Cell Signalling and Metabolic Disorders, Nencki Institute of Experimental Medicine, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kozinski
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.affiliation: Laboratory of Cell Signalling and Metabolic Disorders, Nencki Institute of Experimental Medicine, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Janikiewicz
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.|University Hospital, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szopa
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Tracz
authors.affiliation: Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Borowiec
authors.affiliation: Department of Paediatric Diabetology, Medical University of Silesia, Katowice, Poland.
authors.forename: Przemyslawa
authors.initials: P
authors.lastname: Jarosz-Chobot
authors.affiliation: Department of Paediatrics, Diabetology and Endocrinology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Mysliwiec
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szadkowska
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.|University Hospital, Krakow, Poland.
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
authors.affiliation: Laboratory of Cell Signalling and Metabolic Disorders, Nencki Institute of Experimental Medicine, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dobrzyn
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
mesh_terms: D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D006442:Glycated Hemoglobin; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D035683:MicroRNAs; D034741:RNA, Small Interfering; C517652:hemoglobin A1c protein, human
keywords: HNF; MODY; Monogenic diabetes; Transcription factors; microRNA