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

Juan R. Alvarez-Dominguez, Zhiqiang Bai, Dan Xu, Bingbing Yuan, Kinyui Alice Lo, Myeong Jin Yoon, Yen Ching Lim, Marko Knoll, Nikolai Slavov, Shuai Chen, Peng Chen, Harvey F. Lodish, Lei Sun

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)764-776
Number of pages13
JournalCell Metabolism
Volume21
Issue number5
DOIs
StatePublished - May 5 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

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