Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Sciences University, Portland, OR, 97239, USA.
Clin Epigenetics. 2020 Nov 23;12(1):181. doi: 10.1186/s13148-020-00970-x.
Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.
SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two-sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.
In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.
正常体重多囊卵巢综合征（PCOS）女性在体内表现出脂肪抵抗，伴有皮下（SC）腹部脂肪干细胞（ASC）向脂肪细胞分化的增强，体外每细胞脂质积累加速。本研究在体外研究正常体重 PCOS 与年龄和体重指数匹配的正常排卵（对照）女性的 SC 腹部 ASC 分化为脂肪细胞过程中的染色质可及性、RNA 表达和脂肪酸（FA）合成，以研究 PCOS 和对照 ASC 在脂肪生成过程中的表观遗传/遗传特征和功能改变。
与对照组相比，PCOS 女性的 SC 腹部 ASC 在脂肪生成过程中表现出动态染色质可及性，从第 0 天的染色质可及性显著降低到第 12 天的染色质可及性增加，在第 0、3 和 12 天富集了 AP-1 亚家族转录因子（TF）的结合基序。在 PCOS 与对照组细胞中，调节脂肪细胞分化（PPARγ、CEBPα、AGPAT2）和功能（ADIPOQ、FABP4、LPL、PLIN1、SLC2A4）的基因表达在第 3、7 和 12 天增加了两到六倍，而涉及 Wnt 信号的基因（FZD1、SFRP1 和 WNT10B）则减少。在这些时间点，PCOS 细胞的差异基因表达涉及三酰甘油合成、脂质氧化、游离脂肪酸β氧化以及 TCA 循环的氧化磷酸化，TGFB1 是一个重要的上游调节剂。在第 12 天的脂肪生成过程中，涉及脂肪细胞分化和功能、Wnt 信号以及三酰甘油合成功能组的 12 个基因的染色质可及性增加与 RNA 表达之间存在广泛的对应关系。
在正常体重 PCOS 女性中，SC 腹部 ASC 在脂肪生成过程中的动态染色质重塑可能增强脂肪生成基因表达，作为促进更大脂肪储存的程序化机制。
