Dynamic transcriptome changes during adipose tissue energy expenditure reveal critical roles for long noncoding RNA regulators

Zhiqiang Bai; Xiao-Ran Chai; Myeong Jin Yoon; Hye-Jin Kim; Kinyui Alice Lo; Zhi-Chun Zhang; Dan Xu; Diana Teh Chee Siang; Arcinas Camille Esther Walet; Shao-Hai Xu; Sook-Yoong Chia; Peng Chen; Hongyuan Yang; Sujoy Ghosh; Lei Sun

doi:10.1371/journal.pbio.2002176

Dynamic transcriptome changes during adipose tissue energy expenditure reveal critical roles for long noncoding RNA regulators

PLoS Biol. 2017 Aug 1;15(8):e2002176. doi: 10.1371/journal.pbio.2002176. eCollection 2017 Aug.

Authors

Zhiqiang Bai^{1

2}, Xiao-Ran Chai¹, Myeong Jin Yoon¹, Hye-Jin Kim¹, Kinyui Alice Lo^{1

3}, Zhi-Chun Zhang¹, Dan Xu¹, Diana Teh Chee Siang¹, Arcinas Camille Esther Walet¹, Shao-Hai Xu⁴, Sook-Yoong Chia¹, Peng Chen⁴, Hongyuan Yang⁵, Sujoy Ghosh¹, Lei Sun^{1

3}

Affiliations

¹ Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
² State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
³ Institute of Molecular and Cell Biology, Singapore, Singapore.
⁴ Division of Bioengineering, School of Chemical & Biomedical Engineering, Nanyang Technological University, Singapore, Singapore.
⁵ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.

Abstract

Enhancing brown fat activity and promoting white fat browning are attractive therapeutic strategies for treating obesity and associated metabolic disorders. To provide a comprehensive picture of the gene regulatory network in these processes, we conducted a series of transcriptome studies by RNA sequencing (RNA-seq) and quantified the mRNA and long noncoding RNA (lncRNA) changes during white fat browning (chronic cold exposure, beta-adrenergic agonist treatment, and intense exercise) and brown fat activation or inactivation (acute cold exposure or thermoneutrality, respectively). mRNA-lncRNA coexpression networks revealed dynamically regulated lncRNAs to be largely embedded in nutrient and energy metabolism pathways. We identified a brown adipose tissue-enriched lncRNA, lncBATE10, that was governed by the cAMP-cAMP response element-binding protein (Creb) axis and required for a full brown fat differentiation and white fat browning program. Mechanistically, lncBATE10 can decoy Celf1 from Pgc1α, thereby protecting Pgc1α mRNA from repression by Celf1. Together, these studies provide a comprehensive data framework to interrogate the transcriptomic changes accompanying energy homeostasis transition in adipose tissue.

MeSH terms

Adipose Tissue / metabolism*
Animals
CELF1 Protein / metabolism*
Cell Differentiation
Cyclic AMP / metabolism
Cyclic AMP Response Element-Binding Protein / metabolism
Energy Metabolism*
Gene Expression Regulation
HEK293 Cells
Humans
Male
Mice, Inbred C57BL
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
Primary Cell Culture
RNA, Long Noncoding / metabolism*
Signal Transduction
Transcriptome

Substances

CELF1 Protein
Cyclic AMP Response Element-Binding Protein
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
RNA, Long Noncoding
Cyclic AMP

Grants and funding

National Medical Research Council http://www.nmrc.gov.sg/content/nmrc_internet/home.html (grant number NMRC/CBRG/0101/2016). Received by SUN L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Medical Research Council http://www.nmrc.gov.sg/content/nmrc_internet/home.html (grant number NMRC/CBRG/0070/2014). Received by SUN L and Chen P. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Singapore Ministry of Education https://www.moe.gov.sg/ (grant number MOE2014-T3-1-006). Supported by by the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, received by SUN L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Singapore NRF fellowship https://www.nrf.gov.sg/funding-grants/nrf-fellowship-and-nrf-investigatorship (grant number NRF-2011NRF-NRFF 001-025). Received by SUN L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.