Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
University of Adelaide Bioinformatics Hub, University of Adelaide, Adelaide, Australia.
Sci Rep. 2019 Aug 19;9(1):11966. doi: 10.1038/s41598-019-48333-8.
Progesterone receptor (PGR) co-ordinately regulates ovulation, fertilisation and embryo implantation through tissue-specific actions, but the mechanisms for divergent PGR action are poorly understood. Here we characterised PGR activity in mouse granulosa cells using combined ChIP-seq for PGR and H3K27ac and gene expression microarray. Comparison of granulosa, uterus and oviduct PGR-dependent genes showed almost complete tissue specificity in PGR target gene profiles. In granulosa cells 82% of identified PGR-regulated genes bound PGR within 3 kb of the gene and PGR binding sites were highly enriched in proximal promoter regions in close proximity to H3K27ac-modified active chromatin. Motif analysis showed highly enriched PGR binding to the PGR response element (GnACAnnnTGTnC), but PGR also interacted significantly with other transcription factor binding motifs. In uterus PGR showed far more tendency to bind intergenic chromatin regions and low evidence of interaction with other transcription factors. This is the first genome-wide description of PGR action in granulosa cells and systematic comparison of diverse PGR action in different reproductive tissues. It clarifies finely-tuned contextual PGR-chromatin interactions with implications for more targeted reproductive medicine.
孕激素受体（PGR）通过组织特异性作用协同调节排卵、受精和胚胎着床，但 PGR 作用的分歧机制尚不清楚。在这里，我们使用结合了 PGR 和 H3K27ac 的 ChIP-seq 以及基因表达微阵列，对小鼠颗粒细胞中的 PGR 活性进行了表征。比较颗粒细胞、子宫和输卵管中 PGR 依赖性基因发现，PGR 靶基因谱在组织特异性上几乎完全一致。在颗粒细胞中，82%鉴定出的 PGR 调控基因在基因的 3kb 内与 PGR 结合，PGR 结合位点在靠近 H3K27ac 修饰的活性染色质的近端启动子区域高度富集。基序分析表明 PGR 与 PGR 反应元件（GnACAnnnTGTnC）高度结合，但 PGR 也与其他转录因子结合基序显著相互作用。在子宫中，PGR 更倾向于结合基因间染色质区域，与其他转录因子相互作用的证据很少。这是对颗粒细胞中 PGR 作用的首次全基因组描述，以及对不同生殖组织中不同 PGR 作用的系统比较。它阐明了上下文 PGR-染色质相互作用的精细调控，对更有针对性的生殖医学具有重要意义。
