MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes.
BACKGROUND
MicroRNAs (miRNAs) are non-coding RNA molecules involved in post-transcriptional control of gene expression of a wide number of genes, including those involved in glucose homeostasis. Type 2 diabetes (T2D) is characterized by hyperglycaemia and defects in insulin secretion and action at target tissues. We sought to establish differences in global miRNA expression in two insulin-target tissues from inbred rats of spontaneously diabetic and normoglycaemic strains.


METHODS
We used a miRNA microarray platform to measure global miRNA expression in two insulin-target tissues: liver and adipose tissue from inbred rats of spontaneously diabetic (Goto-Kakizaki [GK]) and normoglycaemic (Brown-Norway [BN]) strains which are extensively used in genetic studies of T2D. MiRNA data were integrated with gene expression data from the same rats to investigate how differentially expressed miRNAs affect the expression of predicted target gene transcripts.


RESULTS
The expression of 170 miRNAs was measured in liver and adipose tissue of GK and BN rats. Based on a p-value for differential expression between GK and BN, the most significant change in expression was observed for miR-125a in liver (FC = 5.61, P = 0.001, Padjusted = 0.10); this overexpression was validated using quantitative RT-PCR (FC = 13.15, P = 0.0005). MiR-125a also showed over-expression in the GK vs. BN analysis within adipose tissue (FC = 1.97, P = 0.078, Padjusted = 0.99), as did the previously reported miR-29a (FC = 1.51, P = 0.05, Padjusted = 0.99). In-silico tools assessing the biological role of predicted miR-125a target genes suggest an over-representation of genes involved in the MAPK signaling pathway. Gene expression analysis identified 1308 genes with significantly different expression between GK and BN rats (Padjusted < 0.05): 233 in liver and 1075 in adipose tissue. Pathways related to glucose and lipid metabolism were significantly over-represented among these genes. Enrichment analysis suggested that differentially expressed genes in GK compared to BN included more predicted miR-125a target genes than would be expected by chance in adipose tissue (FDR = 0.006 for up-regulated genes; FDR = 0.036 for down-regulated genes) but not in liver (FDR = 0.074 for up-regulated genes; FDR = 0.248 for down-regulated genes).


CONCLUSIONS
MiR-125a is over-expressed in liver in hyperglycaemic GK rats relative to normoglycaemic BN rats, and our array data also suggest miR-125a is over-expressed in adipose tissue. We demonstrate the use of in-silico tools to provide the basis for further investigation of the potential role of miR-125a in T2D. In particular, the enrichment of predicted miR-125a target genes among differentially expressed genes has identified likely target genes and indicates that integrating global miRNA and mRNA expression data may give further insights into miRNA-mediated regulation of gene expression.
Herrera
Blanca M
BM
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. blanca@well.ox.ac.uk
Lockstone
Helen E
HE
Taylor
Jennifer M
JM
Wills
Quin F
QF
Kaisaki
Pamela J
PJ
Barrett
Amy
A
Camps
Carme
C
Fernandez
Christina
C
Ragoussis
Jiannis
J
Gauguier
Dominique
D
McCarthy
Mark I
MI
Lindgren
Cecilia M
CM
Bioinformatics. 2002;18 Suppl 1:S96-104
12169536
Am J Physiol. 1996 Oct;271(4 Pt 1):E755-62
8897865
Nature. 2005 Dec 1;438(7068):685-9
16258535
Science. 2004 Apr 23;304(5670):594-6
15105502
BMC Genomics. 2009 Feb 05;10:63
19196459
Mol Endocrinol. 2007 Nov;21(11):2785-94
17652184
Curr Opin Plant Biol. 2004 Oct;7(5):512-20
15337093
Science. 2002 Sep 20;297(5589):2056-60
12154197
Nat Genet. 2005 May;37(5):495-500
15806104
Nat Genet. 1996 Jan;12(1):38-43
8528248
Nature. 2005 Feb 17;433(7027):769-73
15685193
Mol Endocrinol. 2000 Oct;14(10):1557-69
11043572
J Biol Chem. 2007 Jan 12;282(2):1479-86
17110380
PLoS Biol. 2004 Nov;2(11):e363
15502875
Clin Cancer Res. 2008 May 1;14(9):2690-5
18451233
Mol Cell. 2007 Jul 6;27(1):91-105
17612493
Nat Genet. 2007 May;39(5):666-72
17435758
PLoS One. 2008 Apr 23;3(4):e1989
18431476
Science. 2001 Oct 26;294(5543):853-8
11679670
Nature. 2004 Nov 11;432(7014):226-30
15538371
Genome Biol. 2007;8(1):R3
17204154
Mamm Genome. 2006 Feb;17(2):129-46
16465593
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:67-73
17919180
Biochim Biophys Acta. 2008 Nov;1779(11):697-701
18655850
Mol Cancer. 2006 Jun 19;5:24
16784538
J Biol Chem. 2007 Jul 6;282(27):19575-88
17462994
Mol Endocrinol. 2003 Mar;17(3):487-97
12554784
PLoS One. 2008 Aug 13;3(8):e2962
18698428
Genome Biol. 2004;5(10):R80
15461798
Methods Mol Biol. 2006;342:101-13
16957370
Nature. 2008 Sep 4;455(7209):58-63
18668040
Stat Med. 1990 Jul;9(7):811-8
2218183
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
16477010
Nucleic Acids Res. 2006 Mar 20;34(5):1646-52
16549876
Nature. 2004 Sep 16;431(7006):350-5
15372042
Cell. 2003 Dec 26;115(7):787-98
14697198
Science. 2007 Dec 21;318(5858):1931-4
18048652
J Biol Chem. 2006 Sep 15;281(37):26932-42
16831872
Methods. 2001 Dec;25(4):402-8
11846609
Mol Cell Biol. 2005 Nov;25(21):9198-208
16227573
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
10592173
Stat Appl Genet Mol Biol. 2004;3:Article3
16646809
Cell. 2004 Jan 23;116(2):281-97
14744438
Nature. 2008 Sep 4;455(7209):64-71
18668037
Genome Biol. 2003;5(1):R1
14709173
Methods. 2003 Dec;31(4):265-73
14597310
Nat Genet. 2009 Jan;41(1):18-24
19079260