The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Context is all - Characterisation of progesterone receptor-chromatin binding properties in mouse reproductive tissues and its implication of tissue-specific gene expression (#359)

Thao D Dinh 1 , Jimmy Breen 1 2 , Lisa K Akison 3 , Francesco J DeMayo 4 , Hannah M Brown 1 5 6 , Rebecca L Robker 1 , Darryl L Russell 1
  1. Robinson Research Institute, Adelaide, South Australia, Australia
  2. University of Adelaide Bioinformatics Hub, Adelaide, South Australia
  3. Child Health Research Centre, South Brisbane, Queensland, Australia
  4. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
  5. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  6. Australian Research Council Centre for Nanoscale Biophotonics, Adelaide, South Australia, Australia

Progesterone receptor (PGR), the nuclear receptor transcription factor activated by progesterone, regulates vastly different tissue-specific processes in each organ of the reproductive tract, enabling temporal coordination of ovulation, fertilisation and implantation. Ligand activated PGR interacts with chromatin through specific sequence motifs in order to regulate gene expression; however, the mechanism through which it regulates different gene sets in different tissues is still poorly understood. In this study, we provide the first genome-wide description of PGR action in peri-ovulatory mouse granulosa cells using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). We found more than 15000 PGR binding sites in granulosa cells, the majority of which were enriched in proximal promoter regions and within close proximity to H3K27ac-bound chromatin. Motif analysis indicated that while the PGR response element was highly targeted, PGR also interacted with other transcription factor binding motifs. Using a gene expression microarray on wild type and Pgr-null mice we identified 61 significant PGR-dependent genes in granulosa cells, 82% of which possessed PGR binding in ChIP-seq. We also performed a systematic comparison of PGR action in the reproductive tract. We compared PGR-regulated genes between granulosa, uterus and oviduct, showing a high level of tissue specificity in PGR target gene profiles with no PGR-regulated genes found in common between all three tissues. We performed a parallel analysis of our new granulosa cell ChIP-seq with uterus ChIP-seq data, illustrating distinct cistromes and PGR-gene interaction properties between the two tissue types. These findings indicate that PGR relies on interaction with unique co-modulators in each tissue in order to achieve tissue specificity. Our study offers further understanding of the finely-tuned context-specific roles of PGR across the reproductive tract with implications on contraceptive and cancer therapeutics, while also revealing potential targets for the management of anovulatory infertility.