Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Genetics

Background:

• Embryonic stem cells (ESCs) can self-organize into blastocyst-like structures (blastoids).
• Blastoids are valuable models for studying early embryogenesis.
• Intrinsic regulators of blastoid formation are largely unknown.

Purpose of the Study:

• To identify intrinsic regulators governing blastoid formation.
• To understand the role of these regulators in early embryonic development.
• To characterize the molecular mechanisms underlying blastoid development.

Main Methods:

• Development of metrics to grade blastoid resemblance to mouse blastocysts.
• Analysis of differential gene regulon activation in blastoids.
• Functional studies involving abrogation and activation of specific genes (Nr1h2).
• Integrative multi-omics analyses (transcriptome, epigenome, chromatin accessibility).

Main Results:

• Identified an intrinsic program crucial for blastoids and blastocysts across species.
• Nuclear receptor subfamily 1, group H, member 2 (Nr1h2) is essential for blastoid formation.
• Nr1h2 activation induces a unique pluripotency state in ESCs, promoting blastoid formation with enhanced in vivo implantation and lineage contribution.
• Nr1h2 regulates genes involved in embryonic lineage specification and SINE-B1 transposable elements.

Conclusions:

• Nr1h2 is a key intrinsic regulator of blastoid and early embryo development.
• The Nr1h2-centered program governs lineage specification and developmental potential.
• This study provides insights into the fundamental mechanisms of early embryogenesis using stem cell-based models.