# Ovulatory Signal-Driven H3K4me3 and H3K27ac Remodeling in Mural Granulosa Cells Orchestrates Oocyte Maturation and Ovulation

## TL;DR

The study reveals how histone modifications H3K4me3 and H3K27ac regulate gene activity in granulosa cells during ovulation, influencing oocyte maturation.

## Contribution

The study identifies H3K27ac-marked super-enhancers as a novel regulatory mechanism for LH-induced transcriptional activation in mural granulosa cells.

## Key findings

- LH/hCG induces dynamic changes in H3K4me3 and H3K27ac, coordinating gene expression in mural granulosa cells.
- Super-enhancers (SEs) are critical for amplifying gene activation in response to ovulatory signals.
- Pharmacological inhibition confirms that chromatin remodeling via these histone marks controls oocyte maturation and ovulation.

## Abstract

What are the main findings?
During ovulatory signal-induced ovulation, a precisely timed transcriptional reprogramming in mural granulosa cells (MGCs) is evoked, with distinct temporal waves that reflect the progression from oocyte maturation to ovulatory response.H3K4me3 and H3K27ac represent two core histone-modification programs underlying LH-induced transcription. H3K4me3 activates target gene expression primarily by enriching in gene promoter regions; H3K27ac regulates MGCs transcription by establishing enhancers, especially SEs.

During ovulatory signal-induced ovulation, a precisely timed transcriptional reprogramming in mural granulosa cells (MGCs) is evoked, with distinct temporal waves that reflect the progression from oocyte maturation to ovulatory response.

H3K4me3 and H3K27ac represent two core histone-modification programs underlying LH-induced transcription. H3K4me3 activates target gene expression primarily by enriching in gene promoter regions; H3K27ac regulates MGCs transcription by establishing enhancers, especially SEs.

What are the implications of the main findings?
Our study demonstrates that super-enhancers (SEs) constitute a key regulatory axis through which the ovulatory signal amplifies gene activation in MGCs.The integration of temporal transcriptional changes with dynamic promoter and SE remodeling provides a framework for how gonadotropins coordinate MGC function through chromatin architecture, offering new mechanistic insights into the epigenetic orchestration of follicular development.

Our study demonstrates that super-enhancers (SEs) constitute a key regulatory axis through which the ovulatory signal amplifies gene activation in MGCs.

The integration of temporal transcriptional changes with dynamic promoter and SE remodeling provides a framework for how gonadotropins coordinate MGC function through chromatin architecture, offering new mechanistic insights into the epigenetic orchestration of follicular development.

Ovulation and granulosa cell luteinization are induced by ovulatory signals, including luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Histone modifications enable rapid, signal-responsive transcriptional reprogramming. However, the effects of LH/hCG-induced histone modification changes on the mural granulosa cells (MGCs) function remain to be fully elucidated. By mining public datasets we integrated transcriptomic and histone-modification profiles of MGCs across the ovulatory interval and tracked LH/hCG-driven gene expression at three time points (0, 4, and 12 h after-hCG). During oocyte maturation, the 4 h LH-surge constitutes a critical window for meiotic resumption, during which many genes display rapid transcriptional changes followed by a return to baseline levels. Early-response genes are enriched for cell locomotion, inflammatory responses, the activation of signaling pathways, and histone modifications. Furthermore, LH/hCG-induced transcriptome remodeling is highly correlated with dynamic gains or losses of H3K4me3 and H3K27ac. Notably, we discovered for the first time that H3K27ac marks super-enhancers (SEs) that regulate LH/hCG-induced transcriptional activation in MGCs. Finally, through complementary in vitro and in vivo pharmacological inhibition, we demonstrate that LH/hCG governs oocyte maturation and ovulation by reshaping the MGC transcriptome via H3K4me3- and H3K27ac-dependent chromatin remodeling. In summary, our study advances the understanding of how gonadotropins regulate MGC function and oocyte maturation through histone-modification-mediated transcriptional control.