Shoucri Bassem M, Martinez Eric S, Abreo Timothy J, Hung Victor T, Moosova Zdena, Shioda Toshi, Blumberg Bruce
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-2300.
Medical Scientist Training Program, University of California, Irvine, Irvine, California 92697.
Endocrinology. 2017 Oct 1;158(10):3109-3125. doi: 10.1210/en.2017-00348.
Developmental exposure to environmental factors has been linked to obesity risk later in life. Nuclear receptors are molecular sensors that play critical roles during development and, as such, are prime candidates to explain the developmental programming of disease risk by environmental chemicals. We have previously characterized the obesogen tributyltin (TBT), which activates the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR) to increase adiposity in mice exposed in utero. Mesenchymal stem cells (MSCs) from these mice are biased toward the adipose lineage at the expense of the osteoblast lineage, and MSCs exposed to TBT in vitro are shunted toward the adipose fate in a PPARγ-dependent fashion. To address where in the adipogenic cascade TBT acts, we developed an in vitro commitment assay that permitted us to distinguish early commitment to the adipose lineage from subsequent differentiation. TBT and RXR activators (rexinoids) had potent effects in committing MSCs to the adipose lineage, whereas the strong PPARγ activator rosiglitazone was inactive. We show that activation of RXR is sufficient for adipogenic commitment and that rexinoids act through RXR to alter the transcriptome in a manner favoring adipogenic commitment. RXR activation alters expression of enhancer of zeste homolog 2 (EZH2) and modifies genome-wide histone 3 lysine 27 trimethylation (H3K27me3) in promoting adipose commitment and programming subsequent differentiation. These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate.
发育过程中暴露于环境因素与日后患肥胖症的风险有关。核受体是分子传感器，在发育过程中发挥关键作用，因此是解释环境化学物质导致疾病风险的发育编程的主要候选因素。我们之前已对致肥胖物三丁基锡（TBT）进行了表征，它可激活核受体过氧化物酶体增殖物激活受体γ（PPARγ）和视黄酸X受体（RXR），从而增加子宫内暴露小鼠的肥胖程度。这些小鼠的间充质干细胞（MSC）偏向脂肪谱系，而成骨细胞谱系则受到抑制，体外暴露于TBT的MSC以PPARγ依赖的方式转向脂肪命运。为了确定TBT在脂肪生成级联反应中的作用位点，我们开发了一种体外定向分化试验，使我们能够区分对脂肪谱系的早期定向与随后的分化。TBT和RXR激活剂（类视黄醇）在使MSC定向分化为脂肪谱系方面具有显著作用，而强效PPARγ激活剂罗格列酮则无此作用。我们表明，RXR的激活足以实现脂肪生成定向，类视黄醇通过RXR发挥作用，以有利于脂肪生成定向的方式改变转录组。RXR激活会改变zeste同源物2（EZH2）的表达，并在促进脂肪定向和调控随后的分化过程中改变全基因组组蛋白3赖氨酸27三甲基化（H3K27me3）。这些数据为RXR和EZH2在MSC谱系特化中的作用提供了见解，并揭示了TBT等内分泌干扰化学物质如何重编程干细胞命运。
