Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis.
MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator-activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3'UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs.
Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg; Luxembourg Centre for Systems Biomedicine; University of Luxembourg; Esch-Sur-Alzette, Luxembourg.
Maria
M
Bouvy-Liivrand
Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg; Institute of Biomedicine; School of Medicine; University of Eastern Finland; Kuopio, Finland.
Merja
M
Heinäniemi
Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg.
Elisabeth
E
John
Luxembourg Centre for Systems Biomedicine; University of Luxembourg; Esch-Sur-Alzette, Luxembourg; Saarland University Medical Center; Department of Medicine II; Homburg, Saar, Germany.
Jochen G
JG
Schneider
Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg.
Thomas
T
Sauter
Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg.
Lasse
L
Sinkkonen
D020413:3' Untranslated Regions; D050156:Adipogenesis; D000818:Animals; D001665:Binding Sites; D005786:Gene Expression Regulation; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D018716:Molecular Mimicry; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000378:metabolism*
D020413:3' Untranslated Regions; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D047495:PPAR gamma; D008071:Lipoprotein Lipase
adipocyte differentiation; combinatorial gene regulation; lipoprotein lipase; mathematical modelling; microRNA