FXR and RXRA binding in mouse liver

The Farnesoid-X-Receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with Retinoid-X-Receptor (RXR). FXR is expressed as four isoforms (a1-a4) that drive transcription from IR-1 (inverted repeat-1) DNA motifs. More recently, FXR isoforms a2/a4 were found to activate transcription predominantly from non-canonical ER-2 (everted repeat-2) DNA motifs, mediating most metabolic effects of general FXR activation.Here, we explored whether co-occupancy of FXR and RXR in the mouse liver has an influence on DNA motif binding preference. We found RXR acts as a molecular switch, promoting FXRa2 activation from IR-1 instead of ER-2 motifs. Our results showcase FXR as the first NR with RXR-dependent and independent modes of activation, highlighting a potential new layer of complexity for other RXR-heterodimerizing NRs. Overall design: To investigate their binding profile and co-occupancy, we performed ChIP-seq for FXR and RXRA from male mouse liver Please note that the following sample raw data was analyzed in the current study as described below: Experiment Title Run BioSample GSM1899653 FXRChIP_MVEH8 SRR2541540 SAMN04123807

法尼醇X受体（Farnesoid-X-Receptor, FXR）是一类核受体（nuclear receptor, NR），已知其必须与视黄醇X受体（Retinoid-X-Receptor, RXR）形成异二聚体才能发挥功能。FXR存在a1至a4四种亚型，可介导反向重复序列1（inverted repeat-1, IR-1）DNA基序处的转录激活。近期研究发现，FXR的a2/a4亚型主要通过非经典的同向重复序列2（everted repeat-2, ER-2）DNA基序启动转录激活，该过程介导了整体FXR激活所产生的绝大多数代谢效应。

本研究旨在探究小鼠肝脏中FXR与RXR的共占据是否会影响二者的DNA基序结合偏好。研究发现，RXR可作为分子开关，促使FXRα2转而结合IR-1基序而非ER-2基序以启动激活。本研究结果首次证实FXR是首个兼具RXR依赖型与非依赖型激活模式的核受体，为其他与RXR形成异二聚体的核受体的调控复杂性揭示了潜在的全新研究维度。

整体实验设计：为探究二者的结合谱与共占据情况，我们对雄性小鼠肝脏中的FXR与视黄醇X受体α（Retinoid-X-Receptor alpha, RXRA）进行了染色质免疫共沉淀测序（ChIP-seq）。

请注意，本研究按照如下方式分析了以下样本的原始数据：
| 实验标题 | 测序运行号 | 生物样品号 | GEO样本编号 |
|----------------|------------|--------------|-------------|
| FXRChIP_MVEH8 | SRR2541540 | SAMN04123807 | GSM1899653 |