Esrrb guides naive pluripotent cells through the formative transcriptional programme

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Epigenetics

Background:

• Naive pluripotent epiblast cells transition to a formative state during embryonic development.
• This transition involves significant transcriptional and epigenetic changes, enabling differentiation into all lineages.
• Molecular control of the naive-to-formative state transition remains poorly understood.

Purpose of the Study:

• To investigate the molecular mechanisms controlling the transition of naive epiblast cells to a formative state.
• To determine the role of Estrogen-related receptor beta (ESRRB) in this developmental process.

Main Methods:

• Utilized murine embryonic stem cell models.
• Performed genetic inactivation of the Esrrb gene.
• Conducted computational modeling and genomic analyses.
• Assessed gene expression of mesendoderm, extra-embryonic, and formative markers.
• Evaluated self-organization in 3D and differentiation capacity.

Main Results:

• ESRRB is both required and sufficient for activating formative genes.
• Esrrb inactivation led to aberrant expression of mesendoderm/extra-embryonic markers.
• Loss of Esrrb impaired formative gene expression and 3D self-organization.
• ESRRB directly binds to key formative genes in both naive and formative states.
• Absence of Esrrb resulted in compromised formative stem cell and primordial germ cell generation.

Conclusions:

• ESRRB acts as a crucial initiator of the formative transition.
• ESRRB ensures timely and unbiased multi-lineage differentiation capacity.
• Understanding ESRRB's role provides insights into early embryonic development and stem cell potential.