Nam Kyong Nyon, Mounier Anais, Fitz Nicholas F, Wolfe Cody, Schug Jonathan, Lefterov Iliya, Koldamova Radosveta
Department of Environmental &Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Sci Rep. 2016 Apr 7;6:24048. doi: 10.1038/srep24048.
Bexarotene, a selective agonist for Retinoid X receptors (RXR) improves cognitive deficits and amyloid-β (Aβ) clearance in mice. Here we examine if the effect of bexarotene on RXR cistrome and transcriptomes depend on APOE isoform and Aβ deposition. We found bexarotene increased RXR binding to promoter regions in cortex of APOE3 mice. Rho family GTPases and Wnt signaling pathway were highly enriched in ChIP-seq and RNA-seq datasets and members of those pathways - Lrp1, Lrp5, Sfrp5 and Sema3f were validated. The effect of APOE isoform was compared in APOE3 and APOE4 mice and we found significant overlapping in affected pathways. ChIP-seq using mouse embryonic stem cells and enrichment levels of histone marks H3K4me3 and H3K27me3 revealed that, bexarotene induced epigenetic changes, consistent with increased neuronal differentiation and in correlation with changes in transcription. Comparison of transcriptome in APOE3 and APP/APOE3 mice revealed that amyloid deposition significantly affects the response to bexarotene. In primary neurons, bexarotene ameliorated the damaged dendrite complexity and loss of neurites caused by Aβ42. Finally, we show that the disruption of actin cytoskeleton induced by Aβ42 in vitro was inhibited by bexarotene treatment. Our results suggest a mechanism to establish RXR therapeutic targets with significance in neurodegeneration.
贝沙罗汀是一种视黄酸X受体（RXR）的选择性激动剂，可改善小鼠的认知缺陷和β淀粉样蛋白（Aβ）清除。在此，我们研究贝沙罗汀对RXR顺式作用元件组和转录组的影响是否取决于载脂蛋白E（APOE）异构体和Aβ沉积。我们发现贝沙罗汀增加了RXR与APOE3小鼠皮质中启动子区域的结合。Rho家族GTP酶和Wnt信号通路在染色质免疫沉淀测序（ChIP-seq）和RNA测序（RNA-seq）数据集中高度富集，并且这些通路的成员——低密度脂蛋白受体相关蛋白1（Lrp1）、低密度脂蛋白受体相关蛋白5（Lrp5）、分泌型卷曲相关蛋白5（Sfrp5）和3型分泌性 Semaphorin蛋白F（Sema3f）得到了验证。在APOE3和APOE4小鼠中比较了APOE异构体的作用，我们发现在受影响的通路中有显著重叠。使用小鼠胚胎干细胞进行的ChIP-seq以及组蛋白标记H3K4me3和H3K27me3的富集水平显示，贝沙罗汀诱导了表观遗传变化，这与神经元分化增加一致，并且与转录变化相关。比较APOE3和淀粉样前体蛋白/APOE3（APP/APOE3）小鼠的转录组发现，淀粉样蛋白沉积显著影响对贝沙罗汀的反应。在原代神经元中，贝沙罗汀改善了由Aβ42引起的受损树突复杂性和神经突丢失。最后，我们表明贝沙罗汀处理可抑制体外由Aβ42诱导的肌动蛋白细胞骨架破坏。我们的结果提出了一种建立在神经退行性变中具有重要意义的RXR治疗靶点的机制。
