KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice

Tara I McIntyre¹, Omar Valdez², Nathan P Kochhar³, Brittany Davidson³, Bushra Samad³, Longhui Qiu⁴, Kenneth Hu⁵, Alexis J Combes⁶, Adrian Erlebacher⁷

Affiliations

¹ Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Science, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: adrian.erlebacher@ucsf.edu.

PMID: 39842437
PMCID: PMC11890963 (available on 2026-03-06)
DOI: 10.1016/j.cell.2024.12.019

KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice

Tara I McIntyre et al. Cell. 2025.

. 2025 Mar 6;188(5):1265-1279.e18.

doi: 10.1016/j.cell.2024.12.019. Epub 2025 Jan 21.

Authors

Tara I McIntyre¹, Omar Valdez², Nathan P Kochhar³, Brittany Davidson³, Bushra Samad³, Longhui Qiu⁴, Kenneth Hu⁵, Alexis J Combes⁶, Adrian Erlebacher⁷

Affiliations

¹ Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Science, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: adrian.erlebacher@ucsf.edu.

PMID: 39842437
PMCID: PMC11890963 (available on 2026-03-06)
DOI: 10.1016/j.cell.2024.12.019

Abstract

Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.

Keywords: H3K27me3; KDM6B; epigenetic programming; fibroblasts; mouse pregnancy; parturition; progesterone; uterus.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Rokas A, Mesiano S, Tamam O, LaBella A, Zhang G, and Muglia L (2020). Developing a theoretical evolutionary framework to solve the mystery of parturition initiation. Elife 9. 10.7554/eLife.58343. - DOI - PMC - PubMed
1. Mesiano S. (2015). Chapter 42 - Parturition, Fourth Edition (Academic Press; ).
1. Goldenberg RL, Culhane JF, Iams JD, and Romero R (2008). Epidemiology and causes of preterm birth. Lancet 371, 75–84. 10.1016/S0140-6736(08)60074-4. - DOI - PMC - PubMed
1. Menon R. (2008). Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity. Acta Obstet Gynecol Scand 87, 590–600. 10.1080/00016340802005126. - DOI - PubMed
1. Gross GA, Imamura T, Luedke C, Vogt SK, Olson LM, Nelson DM, Sadovsky Y, and Muglia LJ (1998). Opposing actions of prostaglandins and oxytocin determine the onset of murine labor. Proc Natl Acad Sci U S A 95, 11875–11879. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice

Affiliations

KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases