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

• The lncRNA ADINR is developmentally regulated during adipogenesis
• ADINR promotes adipogenesis by activating C/EBPα transcription in cis
• ADINR activates C/EBPα transcription by an MLL3/4-dependent mechanism
• MLL3/4 recruitment to the C/EBPα promoter requires binding of PA1 to ADINR

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.

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