Journal
RNA BIOLOGY
Volume 11, Issue 1, Pages 76-91Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/rna.27655
Keywords
microRNA; mathematical modelling; combinatorial gene regulation; lipoprotein lipase; adipocyte differentiation
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Funding
- University of Luxembourg
- Fondation National de Luxembourg
- National Research Foundation of Luxembourg (FNR) [AFR 1086506, AFR 1011788, Core 12/BM/3971360]
- German Research Association [DFG 682/3-1]
- European Union [CIG 303682]
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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 3UTR 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.
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