From Stem Cells to Blastoids: Unraveling the Mechanisms of Early Embryonic Development and Gene Silencing

Abstract

Understanding the mechanisms of early embryonic development is essential for understanding the origins of aging and disease. Advancements in the culture of embryonic stem cells have opened new avenues for modeling critical timepoints of early development in vitro, such as blastocyst formation, implantation, and gastrulation. The work presented here shows the development of stem cell derived blastocyst like structures, termed blastoids, from pluripotent stem cell cultures in both humans and animals. Blastoids have increased our understanding of the signaling, genetic and epigenetic requirements for the formation of the early embryo. Finally, our work helps to uncover the critical epigenetic interplay that happens in the epiblast of the blastocyst before and after implantation, by using naïve and primed embryonic stem cells to respectively model these stages. We show that TASOR (transcription activator suppressor), part of the Human Silencing Hub (HUSH) complex, is a co-transcriptional platform for epigenetic and epitranscriptomic silencing. We show how the H3K9me3 deposition in naïve cells is essential for the proper establishment of long-term silencing via DNA methylation in primed or differentiated cells. Moreover, our work uncovers an innate immune checkpoint that is activated upon the exit of naïve pluripotency against endogenous retroviral LINE-1 elements and repeats. Overall, this dissertation provides significant insights into the genetic, epigenetic, immunological and signaling mechanisms of the early embryo, offering new perspectives on the intricate biological processes that govern the earliest stage of mammalian life