Histone Variant H2A.J is a Key Epigenetic Regulator in Human Trophoblast Development [CUT&RUN]

The preimplantation development in eutherian mammals is diverse. However, ethical and technical constraints significantly limit our understanding of the molecular and biochemical pathways governing human development. In this study, we discovered an unexpected, species-specific epigenetic pathway regulated by H2A.J, a largely uncharacterized histone variant in preimplantation development using human Blastoid models, IVF bovine embryos, and in vitro human stem cell models. We discovered that H2A.J is expressed in human and bovine placentas, contrasting with its absence in mice, and that H2A.J is essential for trophoblast expansion and viability in human and bovine. Our findings also revealed that H2A.J is enriched at promoters and introns of genes and interacts with RNA Polymerase I and II and pro-elongation factors, thereby regulating RNA Polymerase elongation and trophoblast maintenance in human embryo development. This study sheds light on a novel chromatin factor crucial for proper development in humans and large mammals, offering insights into the evolution of preimplantation development in eutherians. Our research provides valuable insights into evolutionarily divergent epigenetic mechanisms and biological functions in trophoblast lineage maintenance and transcriptional regulation, laying the groundwork for future investigations into the essential but understudied process of human placentation.