An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Molecular Regulatory Mechanisms

Background:

• Cell fate decisions are complex, involving multiple regulatory layers like chromatin remodeling, DNA methylation, and transcription factor binding.
• The precise coordination of these regulatory dimensions in guiding developmental cell fate remains poorly understood.
• Estrogen related receptor beta (Esrrb) is a known key regulator of pluripotency in mouse embryonic stem cells (mESCs).

Purpose of the Study:

• To quantify multi-dimensional molecular changes in mESCs following the depletion of the pluripotency regulator Esrrb.
• To elucidate the regulatory mechanisms coordinating cell fate decisions by comparing Esrrb and Nanog depletion effects.
• To propose a hierarchical model for pluripotency maintenance and differentiation timing.

Main Methods:

• Quantitative analysis of multi-dimensional molecular changes in mESCs.
• Comparative gene expression analysis after depleting Esrrb and Nanog.
• Meta-analyses of regulatory interactions.

Main Results:

• Depletion of Esrrb in mESCs triggers significant multi-dimensional molecular alterations.
• Comparative analysis revealed interlocked feed-forward loops between Nanog and Esrrb are crucial for regulating the timing of mESC fate decisions.
• Oct4-Sox2 module maintains pluripotency, while the Nanog-Esrrb module governs differentiation timing.

Conclusions:

• A hierarchical regulatory model explains pluripotency maintenance and differentiation timing in mESCs.
• The Nanog-Esrrb module plays a critical role in timing developmental cell fate decisions.
• Understanding these regulatory networks is key to deciphering developmental processes.