Progesterone Activates the Histone Lactylation-Hif1α-glycolysis Feedback Loop to Promote Decidualization.
Decidualization is a progesterone-dependent cellular differentiation process that is essential for establishing pregnancy. Robust activation of glycolysis and lactate synthesis during decidualization is remarkable, but their developmental functions remain largely unknown. Herein, we identify that endometrial lactate production plays a critical role in establishing local histone lactylation, a newly identified histone modification, and is important for ensuring normal decidualization. Enhanced endometrial glycolysis is the hallmark metabolic change and is tightly coupled with H4K12la during decidualization. Inhibition of histone lactylation impaired decidualization, in either physiological conception or in vivo and in vitro induced decidualization models. Mechanistic study based on CUT&Tag and ATAC-seq revealed that a transcriptional factor hypoxia-inducible factor 1 α (Hif1α) is the critical regulatory target of H4K12la, and in turn forms an H4K12la-Hif1α-glycolysis feedback loop to drive decidualization. Moreover, we demonstrate that the loop is directly activated by progesterone during decidualization. Our study not only advances the current knowledge of the role of lactate in regulating uterine function, but also establishes a novel functional link among the major endocrine factors, endometrial metabolic change, and epigenetic modification during endometrial remodeling. These findings present valuable clues to develop clinical intervention strategies to improve pregnancy outcomes following both natural conception and assisted reproduction.
Pubmed ID: 37950883 RIS Download
Research resources used in this publication
- Anti-L-lactyllysine rabbit pAb (RRID:AB_2868521) (antibody)
- H3-celegans (RRID:AB_302613) (antibody)
- Beta Actin Antibody (RRID:AB_2782959) (antibody)
- PR antibody (RRID:AB_2880277) (antibody)
- LDHA-Specific antibody (RRID:AB_10646429) (antibody)
- Anti-L-Lactyl-Histone H4 (Lys12) Rabbit mAb (RRID:AB_2941896) (antibody)
- Lactyl-Histone H3 (Lys18) Rabbit mAb (RRID:AB_2909438) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Anti-L-lactyllysine rabbit pAb (RRID:AB_2868521)
- Beta Actin Antibody (RRID:AB_2782959)
- H3-celegans (RRID:AB_302613)
- PR antibody (RRID:AB_2880277)
- LDHA-Specific antibody (RRID:AB_10646429)
- Lactyl-Histone H3 (Lys18) Rabbit mAb (RRID:AB_2909438)
- Anti-L-Lactyl-Histone H4 (Lys12) Rabbit mAb (RRID:AB_2941896)
Associated grants
- Agency: National Center of Technology Innovation,
Id: NCTIP-XD/B03 - Agency: Beijing Innovation Consortium,
- Agency: Livestock Research System,
Id: BAIC05-2023
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This is a list of tools and resources that we have found mentioned in this publication.
Anti-L-lactyllysine rabbit pAb (antibody)
RRID:AB_2868521
This polyclonal targets lactyllysine
View all literature mentionsBeta Actin Antibody (antibody)
RRID:AB_2782959
This monoclonal targets Beta Actin
View all literature mentionsLDHA-Specific antibody (antibody)
RRID:AB_10646429
This polyclonal targets LDHA-Specific
View all literature mentionsLactyl-Histone H3 (Lys18) Rabbit mAb (antibody)
RRID:AB_2909438
This recombinant monoclonal targets Lactyl-Histone H3 (Lys18)
View all literature mentionsAnti-L-Lactyl-Histone H4 (Lys12) Rabbit mAb (antibody)
RRID:AB_2941896
This monoclonal targets L-Lactyl-Histone H4 (Lys12)
View all literature mentionsAnti-L-lactyllysine rabbit pAb (antibody)
RRID:AB_2868521
This polyclonal targets lactyllysine
View all literature mentionsBeta Actin Antibody (antibody)
RRID:AB_2782959
This monoclonal targets Beta Actin
View all literature mentionsLDHA-Specific antibody (antibody)
RRID:AB_10646429
This polyclonal targets LDHA-Specific
View all literature mentionsAnti-L-Lactyl-Histone H4 (Lys12) Rabbit mAb (antibody)
RRID:AB_2941896
This monoclonal targets L-Lactyl-Histone H4 (Lys12)
View all literature mentionsLactyl-Histone H3 (Lys18) Rabbit mAb (antibody)
RRID:AB_2909438
This recombinant monoclonal targets Lactyl-Histone H3 (Lys18)
View all literature mentions
