Progesterone Activates the Histone Lactylation-Hif1α-glycolysis Feedback Loop to Promote Decidualization

Area of Science:

• Reproductive Biology
• Epigenetics
• Metabolic Regulation

Background:

• Decidualization, a progesterone-driven process, is vital for pregnancy establishment.
• The role of enhanced glycolysis and lactate production during decidualization is not well understood.
• Histone lactylation (H4K12la) is a newly identified epigenetic modification.

Purpose of the Study:

• To investigate the function of endometrial lactate production in decidualization.
• To elucidate the role of histone lactylation in uterine remodeling.
• To identify the molecular mechanisms linking metabolism, epigenetics, and decidualization.

Main Methods:

• In vivo and in vitro decidualization models.
• Histone modification analysis (CUT&Tag).
• Chromatin accessibility assays (ATAC-seq).
• Analysis of gene expression and protein interactions.

Main Results:

• Endometrial lactate production is essential for establishing histone lactylation (H4K12la).
• H4K12la directly regulates the transcriptional factor hypoxia-inducible factor 1 α (Hif1α).
• A H4K12la-Hif1α-glycolysis feedback loop, activated by progesterone, drives decidualization.
• Inhibition of histone lactylation impairs decidualization.

Conclusions:

• Lactate-driven histone lactylation is a critical regulator of endometrial decidualization.
• A novel link between progesterone, endometrial metabolism, and epigenetic modification is established.
• Findings provide potential targets for improving fertility and pregnancy outcomes.