Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos

Area of Science:

• Developmental Biology
• Genetics
• Cell Biology

Background:

• Mammalian embryonic development involves early lineage segregation into inner cell mass (ICM) and trophectoderm (TE).
• Understanding the in vivo regulation of these first cell-fate decisions by transcription factors (TFs) is crucial but challenging.
• Existing TF regulomes are often inferred from cell culture, not early embryos.

Purpose of the Study:

• To investigate transcription factor regulomes during the initial lineage specification in early mouse embryos.
• To elucidate the roles of TFAP2C and NR5A2 in totipotency and early lineage commitment.
• To map TF binding and activation across different developmental phases: pre-initiation, initiation, commitment, and maintenance.

Main Methods:

• In vivo investigation of TF binding and gene activation in early mouse embryos.
• Analysis of TFAP2C and NR5A2 regulomes at totipotent (two- to eight-cell) and blastocyst stages.
• Assessment of gene expression, apoptosis, and cell numbers following TFAP2C deficiency.

Main Results:

• TFAP2C binds and activates both early ICM and TE genes at the totipotent stage ('bipotency activation').
• Tfap2c deficiency leads to downregulation of key ICM and TE genes, causing developmental defects in blastocysts.
• TFAP2C dynamically shifts binding from early ICM genes to late TE and extra-embryonic ectoderm (ExE) genes during commitment.
• NR5A2 also exhibits 'bipotency activation', binding and activating both ICM and TE lineage genes at the eight-cell stage.

Conclusions:

• TFAP2C and NR5A2 play critical roles in regulating the earliest cell-fate decisions in mammalian embryos.
• A unique transcriptional circuitry underlies totipotency, involving adaptable lineage regulators.
• These findings provide novel insights into the in vivo mechanisms governing mammalian embryonic lineage specification.