Background
The placenta is a transient organ essential for fetal growth and maternal adaptation to pregnancy, with lasting consequences for offspring health. Although placental defects are common and underlie numerous pregnancy complications, the molecular mechanisms leading to such complications remain poorly understood. While placental defects manifest late in gestation, they likely arise earlier in development, potentially from disruptions in trophoblast lineage specification. Histone post-translational modifications (PTMs) are sensitive to metabolism and environmental factors and function combinatorially to regulate chromatin states and gene expression. However, existing methods profile individual histone PTMs independently or cannot simultaneously capture the transcriptome, limiting the ability to directly associate combinatorial chromatin states with transcriptional programs during trophoblast development.
Methods
To investigate the epigenetic mechanisms governing early placental development, we use mouse trophectoderm stem cells (mTESCs) and mouse embryonic stem cells (mESCs) as complementary models of extraembryonic and embryonic lineages. We apply newly developed multimodal epigenomic approaches that simultaneously profile multiple histone PTMs and gene expression to define how combinatorial chromatin states emerge during lineage specification and how they relate to transcriptional programs.
Results
Our previous work demonstrated that paternal obesity alters sperm H3K4me3 at developmental and placental genes and predisposes offspring to metabolic dysfunction. In addition, paternal obesity was associated with placental transcriptional changes enriched for hypoxia-related signatures, and altered cellular composition, suggesting disruptions in placental development and trophoblast specification. These findings identified the placenta as a potential mediator linking paternal metabolic health to offspring outcomes. Building on these observations, the present work investigates the lineage-specifying epigenetic mechanisms regulating developmental trajectories and trophoblast identity.
Conclusion
This work aims to define how combinatorial chromatin states regulate gene expression during early placental development and establish a framework for understanding how metabolic and environmental perturbations may disrupt placental function and influence long-term offspring health.