Esrrb Unlocks Silenced Enhancers for Reprogramming to Naive Pluripotency

Area of Science:

• Epigenetics
• Stem Cell Biology
• Transcription Factor Function

Background:

• Transcription factor (TF)-mediated reprogramming to pluripotency is often slow and inefficient due to chromatin accessibility challenges.
• The precise mechanisms by which TFs open repressive chromatin during reprogramming remain incompletely understood.

Purpose of the Study:

• To investigate the role of transcription factors in orchestrating chromatin opening during cellular reprogramming.
• To elucidate the pioneering function of Esrrb in recruiting core pluripotency factors to closed chromatin.

Main Methods:

• Utilized epiblast stem cell reprogramming models.
• Analyzed TF binding dynamics at inactive enhancers.
• Assessed changes in DNA methylation and nucleosome positioning.
• Investigated the role of LIF and p300 in the process.

Main Results:

• Esrrb acts as a pioneer factor, binding to silenced enhancers with stable nucleosomes and hypermethylated DNA.
• Esrrb binding facilitates local DNA demethylation and p300 recruitment in a LIF-dependent manner.
• Nucleosome displacement follows Esrrb binding, allowing recruitment of core pluripotency factors (Oct4, Sox2, Nanog) within approximately 2 days.
• Demonstrated rapid chromatin remodeling driven by TFs.

Conclusions:

• Esrrb plays a critical pioneering role in initiating chromatin accessibility for pluripotency factors.
• TF-mediated chromatin remodeling can overcome stable epigenetic barriers, showcasing epigenetic plasticity.
• This study provides mechanistic insights into the early events of cellular reprogramming.