The pervasiveness of noncoding transcription has revolutionized our understanding of gene regulation. Although not yet fully catalogued in terms of numbers, mammalian genomes express a broad spectrum of, small and long, noncoding RNAs. Whereas small noncoding RNAs like microRNAs and their role in energy metabolism and glucose handling are rather well understood, we have little understanding concerning the metaboregulatory properties of those 10,000s of long noncoding RNAs (lncRNAs) encoded in mammalian genomes. To adress this, we applied deep next-generation sequencing to quantify the expression of lncRNAs in two mouse models of obesity and insulin resistance. Intruigingly, we observed the majority of hepatic lncRNAs being downregulated in obese animals, whereas fasting increased lncRNA expression. Using in silico motif enrichment and ChiP-Seq analyses in coding versus noncoding gene promoters, we observed that noncoding promoters are enriched for binding events of smallMafs, a repressive class of transcription factors. Crucially, hepatic overexpression of smallMafs mimicked the obesity-evoked downregulation of the noncoding transcriptome and caused disturbancies in hepatic lipid handling, whereas antisense-nucleotide-mediated depletion of small Mafs prevented diet-induced obesity. Collectively, we here identified a novel signaling circuit coupling obesity-evoked changes in signal transduction to global regulation of the Noncoding Transcriptome.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology