Background: Early studies have unveiled multiple regulatory functions of circular RNAs (circRNAs); however, accurate detection and quantification of circRNAs, especially in understudied organisms, is unsolved yet. Results:In this study, we developed a new reference-free method, namely Cirit, to de novo detect circRNAs with sequence support from the next generation sequencing (NGS) transcriptome. The Cirit showed remarkable performance in accurate detection and quantification of circRNAs via comparing with current methods from different aspects. Using Cirit, we detected 28,813 nonredundant human circRNAs from 91 transcriptome datasets, as well as 2,385 circRNAs from four understudied organisms.Subsequent analyses found that the majority of human circRNAs expressed spatiotemporally; only a very small portion of circRNAs were back-splice junction (BSJ)-consistent (maximally 5.17%) or sequence-consistent (under 2%). Furthermore, circRNA genesis were relatively flexible that only about 60% of human circRNAs used the canonical GT-AG pattern for back-splice. The inconsistent expression of circRNAs challenges their roles as precise transcriptional regulators. Conclusions:In summary, the reference-free method provides a straightforward and universal way for reliable circRNA research. It will largely boost the successful rate in designing highly specific probes to monitor circRNA behavior in cell. In particular, it brings circRNA research to the organisms that have no genome or draft genome.

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The number of patients with type 2 diabetes mellitus (T2DM), which is mainly characterized by insulin resistance and insulin secretion deficiency, has been soaring in recent years. Accompanied by many other metabolic syndromes, such as cardiovascular diseases, T2DM represents a big challenge to public health and economic development. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that is critical in regulating glucose and lipid metabolism, has been developed as a powerful drug target for T2DM, such as thiazolidinediones (TZDs). Despite thiazolidinediones (TZDs), a class of PPARγ agonists, having been proven to be potent insulin sensitizers, their use is restricted in the treatment of diabetes for their adverse effects. Post-translational modifications (PTMs) have shed light on the selective activation of PPARγ, which shows great potential to circumvent TZDs’ side effects while maintaining insulin sensitization. In this review, we will focus on the potential effects of PTMs of PPARγ on treating T2DM in terms of phosphorylation, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation, and S-nitrosylation. A better understanding of PTMs of PPARγ will help to design a new generation of safer compounds targeting PPARγ to treat type 2 diabetes.

Obesity is a growing global epidemic linked to many diseases, including diabetes, cardiovascular diseases, and musculoskeletal disorders. Exercise can improve bone density and decrease excess bone marrow adipose tissue (BMAT) in obese individuals. However, the mechanism of exercise regulating bone marrow microenvironment remains unclear. This study examines how exercise induces bone marrow remodeling in diet-induced obesity. We employed unbiased RNA-Seq to investigate the effect of exercise on the bone marrow of diet-induced obese male mice. Bone mesenchymal stem cells (BMSCs) were isolated to explore the regulatory effects of exercise in vitro. Our data demonstrated that exercise could slow down the progression of obesity and improve trabecular bone density. RNA-seq data revealed that exercise inhibited secreted phosphoprotein 1 (Spp1), which was shown to mediate bone resorption through mechanosensing mechanisms. Interactome analysis of Spp1 using the HINT database showed that Spp1 interacted with the adipokine adipsin. Moreover, exercise decreased BMAT, which induced osteoclast differentiation and promoted bone loss. Our study reveals that exercise improves the bone marrow microenvironment by at least partially inhibiting the adipsin–Spp1 signaling pathway so as to inhibit the alternative complement system from activating osteoclasts in diet-induced obese mice.

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