Poster Presentation 40th Annual Lorne Genome Conference 2019

­Context is all - Progesterone receptor-chromatin binding properties and implications on tissue-specific gene expression in mouse reproductive tissues (#142)

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

Progesterone receptor (PGR), the nuclear receptor responsive to progesterone, regulates diverse tissue-specific processes in the reproductive tract. In ovarian granulosa cells, PGR is critical for ovulation and female fertility (1). As a transcription factor, PGR modulates target gene expression mainly through interaction with the canonical PGR response element (PRE), but can employ non-canonical pathways in specific cases (2). However, exactly how different gene sets are targeted by PGR leading to diverse tissue-specific functions is still poorly understood. In this study, we provide the first genome-wide characterisation of PGR action in peri-ovulatory mouse granulosa cells in contrast to PGR properties in the oviduct and uterus. PGR ChIP-seq identified more than 15000 PGR DNA binding sites in granulosa cells, 62% of which were enriched in proximal promoter regions and nearly 75% were within close proximity to transcriptionally active chromatins. Motif analysis indicated that while the canonical PRE was highly targeted, PGR also interacted with other transcription factor binding motifs. Parallel analysis of granulosa cells and uterus PGR ChIP-seq illustrated distinctive cistromes, including unique preferences for genomic regions and non-canonical motif binding. Microarray analysis on wild type vs Pgr-null mice showed 61 PGR-dependent genes in granulosa cells, 90% of which possessed PGR binding. A systematic comparison of PGR action in granulosa cells, oviduct and uterus showed a high level of specificity in PGR-regulated downstream gene profiles, with no common genes found between all three tissues. These findings confirm the unique transcriptional regulatory roles of PGR in reproductive tissues and suggest that PGR employs a combination of canonical motif interaction and cooperation with unique co-modulators and genomic regions in order to achieve specificity. Our study offers further understanding of the finely-tuned context-specific roles of PGR across the reproductive tract in particular and highlights the complexity of steroid receptor-transcription factor gene regulation mechanisms in general.

  1. Akison & Robker, Reproduction in domestic animals 47 (2012): 288-296.
  2. Doyle et al., Molecular Endocrinology 18 (2004): 2463-2478.