Transcriptomic analysis reveals regulation of adipogenesis via long non-coding RNA, alternative splicing, and alternative polyadenylation. Transcriptomic analysis reveals regulation of adipogenesis via long non-coding RNA, alternative splicing, and alternative polyadenylation

Obesity is characterized by dysregulated adipogenesis leading to increased number and/or size of adipocytes. Understanding the molecular mechanisms governing regulation of adipogenesis is therefore key to designing therapeutic interventions against obesity. In our study, we analyzed 3’-end sequencing data generated from sequencing of human preadipocytes and adipocytes, as well as data available in publicly available databases, to propose mechanisms of molecular regulation of adipogenesis. We discovered lncRNAs that have not been previously characterized but may be key regulators of both brown and white adipogenesis. We also demonstrated possible mechanisms of direct or indirect regulation of adipogenesis through alternative splicing. Finally, we show that usage of alternative polyadenylation sites of key adipogenesis genes leads to isoform diversity, which can have significant biological consequences on differentiation efficiency. Therefore, our research reveals potential therapeutic avenues for obesity through manipulation of long non-coding RNA levels, alternative splicing as well as the usage of alternative polyadenylation sites. Overall design: To investigate changes in gene expression and alternative polyadenylation during white adipogenesis of primary human preadipocytes (Day 0) to mature adipocytes (Day 14).

肥胖以脂肪生成失调为特征，可导致脂肪细胞数量增多和/或体积增大。因此，阐明调控脂肪生成的分子机制，是开发肥胖治疗干预手段的关键所在。本研究分析了人类前脂肪细胞与成熟脂肪细胞的3'-端测序（3'-end sequencing）数据，以及公开数据库中的相关数据集，旨在揭示脂肪生成的分子调控机制。本研究发现了此前未被表征的长链非编码RNA（long non-coding RNA, lncRNAs），其可能是棕色与白色脂肪生成的关键调控因子。本研究还揭示了通过可变剪接（alternative splicing）直接或间接调控脂肪生成的潜在机制。最后，本研究证实，关键脂肪生成基因的可变多聚腺苷酸化（alternative polyadenylation）位点使用差异会产生转录本多样性，该差异对细胞分化效率具有显著的生物学影响。因此，本研究揭示了通过调控长链非编码RNA水平、可变剪接以及可变多聚腺苷酸化位点使用来治疗肥胖的潜在途径。整体实验设计：探究原代人类前脂肪细胞（培养第0天）向成熟脂肪细胞（培养第14天）进行白色脂肪生成过程中，基因表达与可变多聚腺苷酸化的变化。