Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPα

Abstract

SummaryC/EBPα is a critical transcriptional regulator of adipogenesis. How C/EBPα transcription is itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR (adipogenic differentiation induced noncoding RNA), transcribed from a position ∼450 bp upstream of the C/EBPα gene, that orchestrates C/EBPα transcription in vivo. Depletion of ADINR leads to a severe adipogenic defect that is rescued by overexpression of C/EBPα. Moreover, we reveal that ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes so as to increase H3K4me3 and decrease H3K27me3 histone modification in the C/EBPα locus during adipogenesis. These results show that ADINR plays important roles in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBPα in cis.

Long noncoding RNAs in regulating adipogenesis: new RNAs shed lights on obesity

“…Using mRNA-lncRNA-combined microarray technology, a recent study revealed 1423 differentially expressed lncRNAs on days 0, 3, and 6 of adipogenic differentiation of human mesenchymal stem cells (hMSCs) [46]. One of the highly induced lncRNAs, named ADINR (adipogenic differentiation induced noncoding RNA), was divergently transcribed from a position ~450 bp upstream of the CEBPα gene and was shown to be co-expressed with CEBPα during adipogenic differentiation [46].…”

“…One of the highly induced lncRNAs, named ADINR (adipogenic differentiation induced noncoding RNA), was divergently transcribed from a position ~450 bp upstream of the CEBPα gene and was shown to be co-expressed with CEBPα during adipogenic differentiation [46]. Depletion of ADINR led to a dramatic adipogenic defect, as shown by decreased lipid accumulation and reduced adipogenic transcripts CEBPα, PPARγ, FABP4, and LPL.…”

“…Depletion of ADINR led to a dramatic adipogenic defect, as shown by decreased lipid accumulation and reduced adipogenic transcripts CEBPα, PPARγ, FABP4, and LPL. In addition, lentivirus-mediated ectopic expression of CEBPα enhanced expression of CEBPα as well as other adipogenic markers, and restored the severe adipogenic defects caused by the depletion of endogenous ADINR [46]. Mechanistically, ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes to increase H3K4me3 and decrease H3K27me3 histone modification in the CEBPα locus, resulting in CEBPα activation as well as enhanced adipogenesis [46].…”

“…In addition, lentivirus-mediated ectopic expression of CEBPα enhanced expression of CEBPα as well as other adipogenic markers, and restored the severe adipogenic defects caused by the depletion of endogenous ADINR [46]. Mechanistically, ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes to increase H3K4me3 and decrease H3K27me3 histone modification in the CEBPα locus, resulting in CEBPα activation as well as enhanced adipogenesis [46]. This data demonstrates that ADINR plays important roles in regulating the differentiation of hMSCs into adipocytes by modulating CEBPα in cis, demonstrating a mechanism of lncRNAs regulation of nearby gene expressions.…”

Krüppel-like factor 10 (KLF10) is transactivated by the transcription factor C/EBPβ and involved in early 3T3-L1 preadipocyte differentiation

“…Moreover, C/EBPβ is not the only factor activating C/EBPα and PPARγ expression. For example, the long noncoding RNA ADINR can regulate adipogenesis by transcriptionally activating C/EBPα (36). KLF9 can promote PPARγ transactivation at the middle stage of adipogenesis (19).…”