10.6084/m9.figshare.9198236.v1 Maria Bouvy-Liivrand Maria Bouvy-Liivrand Merja Heinäniemi Merja Heinäniemi Elisabeth John Elisabeth John Jochen G Schneider Jochen G Schneider Thomas Sauter Thomas Sauter Lasse Sinkkonen Lasse Sinkkonen Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis Taylor & Francis Group 2019 microRNA mathematical modelling combinatorial gene regulation lipoprotein lipase adipocyte differentiation 2019-07-31 11:40:00 Journal contribution https://tandf.figshare.com/articles/journal_contribution/Combinatorial_regulation_of_lipoprotein_lipase_by_microRNAs_during_mouse_adipogenesis/9198236 <p>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 (<i>Lpl</i>), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator-activated receptor gamma (<i>Pparg</i>) during 3T3-L1 adipocyte differentiation. More importantly, we show that <i>Lpl</i>, 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 <i>Lpl</i> 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 <i>Lpl</i> 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.</p>