Abstract Background: Caesarean section (CS) increases maternal stress, which may impair placental function and foetal cortisol. 11β-hydroxysteroid dehydrogenase type 2 (HSD2) is crucial for foetal protection by reducing cortisol levels. The HSD11B2 gene, regulated by epigenetic alterations in response to stress, may reduce 11β-HSD2 synthesis, weakening the protective mechanism. This study aims to examine the epigenetic regulation of HSD11B2 in placental trophoblasts after CS-induced stress and sought approaches to restore its function. Aim: The aim of this study was to investigate how stress associated with CS influences the regulation of the placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), with particular focus on the role of epigenetic mechanisms. Objectives: The objective of the study was to investigate how stress affects the regulation of HSD11B2 in the placenta using a multi-omics approach; to identify the impact of stress on the HSD11B2 locus and determine how these changes influence enzyme expression and to examine the relationship between enhancer methylation, 11β-HSD2 activity and cortisol-to-cortisone conversion. Methodology: Spatial transcriptomics, single-cell bisulfite sequencing (scBS-seq) and assay for transposase-accessible chromatin using sequencing were applied to human placental tissues from caesarean deliveries. The primary trophoblast cells were utilised in a CRISPR-dCas9-TET1 system to demethylate a candidate enhancer adjacent to the HSD11B2 locus. Measured parameters included DNA methylation, chromatin accessibility, gene expression, and the conversion of cortisol to cortisone. Results: A hypoxia-sensing enhancer at the HSD11B2 and E1 locus was identified, which was hypermethylated under stress, resulting in decreased chromatin accessibility and reduced 11β-HSD2 expression. The CRISPR-dCas9-TET1 editing method reduced the methylation of enhancers by 78%, redeveloped chromatin accessibility (to 89% of normal) and corrected the cortisol metabolism of trophoblasts. Enhancement following editing was significant in the umbilical vein ratios of cortisol, cortisone and enzyme activity. Conclusion: Epigenetic modification of HSD11B2 during stress disrupts placental cortisol regulation in CS. Targeted epigenetic editing with CRISPR-dCas9-TET1 restores 11 β-HSD2 function, offering a potential therapeutic strategy to protect the foetus in high-risk pregnancies.
Sindi et al. (2026) studied this question.