RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements

Area of Science:

• Developmental Biology
• Molecular Biology
• Genomics

Background:

• Ligand-activated retinoic acid receptors (RARs) are crucial for embryonic cell differentiation.
• RARs inhibit pluripotency genes and activate differentiation genes, but the underlying mechanism is not fully understood.

Purpose of the Study:

• To investigate the dynamic genomic mechanisms of RAR/RXR action during retinoic acid (RA)-induced primitive endoderm (PrE) differentiation.
• To elucidate how RAR/RXR binding site occupancy and composition change during early embryonic cell differentiation.

Main Methods:

• Joint ChIP-seq and mRNA-seq time-series analysis of RAR/RXR binding and gene expression in F9 EC cells over 48 hours of RA treatment.
• In-depth analysis of RAR/RXR binding site dynamics, motif composition, and associated transcription factor binding.

Main Results:

• RAR/RXR receptors undergo genomic redistribution during RA-induced PrE differentiation.
• In undifferentiated cells, RAR/RXR bind to regions with pluripotency factors and DR0 motifs.
• In differentiated cells, RAR/RXR shift to regions enriched with Sox17 binding sites and DR5 motifs.

Conclusions:

• RAR/RXR mediate pluripotent cell differentiation through distinct sets of regulatory regions that change with differentiation status.
• The dynamic genomic interactions of RAR/RXR provide a detailed view of RA's role in triggering differentiation.