The Ovulatory Signal Precipitates LRH-1 Transcriptional Switching Mediated by Differential Chromatin Accessibility

• Published in: Cell reports (Cambridge) 2019-08, Vol.28 (9), p.2443-2454.e4
• Main Authors: Bianco, Stéphanie, Bellefleur, Anne-Marie, Beaulieu, Élaine, Beauparlant, Charles Joly, Bertolin, Kalyne, Droit, Arnaud, Schoonjans, Kristina, Murphy, Bruce D., Gévry, Nicolas
• Format: Article
• Language: English
• Subjects: chromatin; granulosa cell; LRH-1; Nr5a2; ovary; ovulation; transcription
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.088

In the ovary, follicular growth and maturation are complicated processes that involve a series of morphological and physiological changes in oocytes and somatic cells leading to ovulation and luteinization, essential processes for fertility. Given the complexity of ovulation, characterization of genome-wide regulatory elements is essential to understand the mechanisms governing the expression of specific genes in the rapidly differentiating follicle. We therefore employed a systems biology approach to determine global transcriptional mechanisms during the early stages of the ovulatory process. We demonstrate that, following the hormonal signal that initiates ovulation, granulosa cells undergo major modification of distal regulatory elements, which coincides with cistrome reprogramming of the indispensable orphan nuclear receptor liver receptor homolog-1 (LRH-1). This cistromic reorganization correlates with the extensive changes in gene expression in granulosa cells leading to ovulation. Together, our study yields a highly detailed transcriptional map delineating ovarian cell differentiation during the initiation of ovulation. [Display omitted] •The LH signal initiates extensive chromatin remodeling in the ovarian follicle•LRH-1-specific DNA sequence motifs are found in open chromatin domains•Dynamic LRH-1 cistrome reprogramming controls granulosa cells differentiation•LRH-1 directly regulates early events leading to ovulation Bianco et al. evaluate chromatin accessibility, LRH-1 ChIP-seq, and RNA-seq to establish early events in ovarian follicles following the LH surge leading to ovulation. They demonstrate extensive chromatin remodeling and reprogramming of the LRH-1 cistrome and transcriptome. CRE-lox depletion of LRH-1 prevents key ovulatory processes, including cell migration and angiogenesis.