CircRNAs are highly conserved between species and the expression patterns are tissue-specific and developmental stage-specific.
However, with the routine use of high-throughput sequencing technology, circRNAs are expressed in various organisms ( Memczak et al., 2015). At that time, circRNA was considered as rare byproducts or spliced intermediates. In 1979, circRNA was first observed in Hela cells by electron microscopy ( Hsu and Coca-Prados, 1979). CircRNAs are covalently linked non-coding RNAs with neither 5′ caps nor 3’ polyadenylated tails, thus it is more stable than linear RNAs ( Li et al., 2018a). Recently, circRNA emerged as a new type of noncoding RNA. It is known that many miRNAs ( Gharanei et al., 2020) and lncRNA ( Squillaro et al., 2020) regulate brown adipogenesis and thermogenesis. In recent years, a lot of studies have been focusing on noncoding RNAs. Pparγ, Prdm16, and Pgc1α ( Shapira and Seale, 2019). Previous studies have identified numerous protein regulators of brown adipogenesis, e.g. The BAT activity positively correlates with human metabolic rate and reduces energy storage, thus strategies that enhance BAT development and increase BAT activity are considered as possible approaches to combat obesity ( Bhatt et al., 2017).Īdipogenesis is the process through which preadipocytes differentiate into adipocytes. It had been considered that BAT only exists in infants, however recent reports detected functional BAT in adult humans ( Leitner et al., 2017). The WAT, which contains large lipid droplets, is the main place of energy storage, whereas BAT contains plenty of mitochondria and converts chemical energy into heat to maintain body temperature ( Betz and Enerbäck, 2018). Human adipose tissue mainly includes white adipose tissue (WAT) and BAT. Obesity develops when the energy intake is more than the energy expenditure. As obesity is highly associated with metabolic syndromes, such as diabetes, cardiovascular diseases, and even cancer, it severely threatens public health ( Blüher, 2019). In recent years, the number of obese people is increasing rapidly and becoming pandemic. Collectively, we characterized the circRNA expression profiles during brown adipogenesis and provide numerous novel circRNAs candidates for future brown adipogenesis regulating studies. More interestingly, most of the circRNAs contained multiple binding sites for the same miRNA, indicating that they may facilitate functions by acting as microRNA sponges. Bioinformatics predictions showed that DECs contained numerous binding sites of functional miRNAs. For the potential functions of the circRNAs, GO analysis suggested that the decreased circRNAs were enriched in cell proliferation terms, while the increased circRNAs were enriched in development and thermogenic terms.
Experimental validation showed the identified circRNAs could be successfully amplified and the expression levels detected by RNA-seq were reliable. Further, time-series expression analysis showed circRNAs were dynamically expressed, and 117 differential expression circRNAs (DECs) in brown adipogenesis were identified, with 77 upregulated and 40 downregulated. Compared to white adipocytes, nearly 30% of them were specifically expressed in brown adipocytes. Next, we examined the cell-specific and differentiation stage-specific expression of circRNAs. We found the biogenesis of circRNA was significantly related to linear mRNA transcription, meanwhile, almost 70% of circRNAs were generated by alternative back-splicing. We identified 3,869 circRNAs and 36.9% of them were novel. This study determined the circRNA expression profiles across brown adipogenesis (proliferation, early differentiated, and fully differentiated stages) by RNA-seq. Many protein-coding genes, miRNAs, and lncRNAs have been investigated in BAT development, however, the expression patterns and functions of circRNA in brown adipogenesis have not been reported yet.
Pengpeng Zhang 1, Mingxuan Sheng 1, Chunyu Du 1, Zhe Chao 2, Haixia Xu 1, Xiaofang Cheng 1, Cencen Li 1* and Yongjie Xu 1,3*
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