De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development

• Published in: Cell metabolism Vol. 21; no. 5; pp. 764 - 776
• Main Authors: Alvarez-Dominguez, Juan R., Bai, Zhiqiang, Xu, Dan, Yuan, Bingbing, Lo, Kinyui Alice, Yoon, Myeong Jin, Lim, Yen Ching, Knoll, Marko, Slavov, Nikolai, Chen, Shuai, Chen, Peng, Lodish, Harvey F., Sun, Lei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-05-2015
• Subjects: Adipocytes, Brown - cytology; Adipocytes, Brown - metabolism; Adipogenesis; Adipose Tissue, Brown - cytology; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animals; Base Sequence; Cell Line; Cells, Cultured; Humans; Mice; RNA, Long Noncoding - genetics; Thermogenesis; Transcriptional Activation; Transcriptome
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.04.003

Brown adipose tissue (BAT) protects against obesity by promoting energy expenditure via uncoupled respiration. To uncover BAT-specific long non-coding RNAs (lncRNAs), we used RNA-seq to reconstruct de novo transcriptomes of mouse brown, inguinal white, and epididymal white fat and identified ∼1,500 lncRNAs, including 127 BAT-restricted loci induced during differentiation and often targeted by key regulators PPARγ, C/EBPα, and C/EBPβ. One of them, lnc-BATE1, is required for establishment and maintenance of BAT identity and thermogenic capacity. lnc-BATE1 inhibition impairs concurrent activation of brown fat and repression of white fat genes and is partially rescued by exogenous lnc-BATE1 with mutated siRNA-targeting sites, demonstrating a function in trans. We show that lnc-BATE1 binds heterogeneous nuclear ribonucleoprotein U and that both are required for brown adipogenesis. Our work provides an annotated catalog for the study of fat depot-selective lncRNAs and establishes lnc-BATE1 as a regulator of BAT development and physiology.
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•Deep RNA profiling uncovers >400 adipose tissue-selective lncRNA genes•Adipose-selective lncRNAs are dynamically regulated by common adipogenic factors•lnc-BATE1 is needed for maturation and maintenance of brown thermogenic adipocytes•lnc-BATE1 mediates trans-activation of brown fat and -repression of white fat genes
Alvarez-Dominguez et al. report an annotated catalog of lncRNAs active across adipose tissues, uncovering >100 brown fat-selective and dynamically regulated lncRNAs. One of them, lnc-BATE1, acts in trans to sustain the core brown fat gene program and repress white fat genes, modulating development and maintenance of brown thermogenic adipocytes.