SMARCA2/4-Dependent Chromatin Remodelling Establishes Gene Regulatory Programs in Early Human Embryos and Blastoids

Abstract Gene regulatory networks establish cell identity during development by regulating transcription factor binding at cis-regulatory elements, many of which require chromatin remodelers for accessibility. Although these key principles of gene regulation in mammalian development have emerged, the contribution of chromatin remodellers to early human embryogenesis remains unclear. Here, we show that the SWI/SNF ATPases SMARCA2 and SMARCA4 are essential for establishing gene regulatory programs and cell identity in human pre-implantation development by facilitating enhancer accessibility. Using both human blastoids and human blastocysts, we find that loss of SMARCA2/4 disrupts blastoid epiblast identity, enhances trophectoderm initiation, and impairs inner cell mass formation and developmental progression. Integrative single-cell chromatin accessibility and transcriptome profiling in blastoids reveals that SMARCA2/4 safeguard naïve epiblast and trophectoderm programs by maintaining enhancer and transcription factor binding motif accessibility. These findings identify SWI/SNF chromatin remodellers as critical regulators of embryonic lineage specification during human pre-implantation development. Competing Interest Statement The KU Leuven University, Belgium, has filed a patent application PCT/EP2023/073949 describing the protocols for inducing EXMCs using naive human pluripotent stem cells. V.P. is a co-inventor of this patent. All other authors declare no competing interests.