RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Cellular plasticity and adaptation rely on coordinated gene transcription.
• The precise mechanisms of context-specific transcriptional regulation by transcription factors are not fully understood.
• Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulator of adaptive transcription.

Purpose of the Study:

• To investigate the role of PGC-1α's C-terminal domain in transcriptional regulation.
• To elucidate the mechanisms by which PGC-1α orchestrates complex transcriptional networks.
• To explore the role of liquid-liquid phase separation in PGC-1α-mediated transcription.

Main Methods:

• Biochemical assays to study PGC-1α interactions with RNA and proteins.
• Chromatin immunoprecipitation to assess PGC-1α recruitment.
• Microscopy to visualize nuclear condensates in mouse and human skeletal muscle cells.

Main Results:

• The C-terminal domain of PGC-1α directly binds RNA and facilitates the assembly of multiprotein complexes.
• These PGC-1α-containing complexes are recruited to chromatin within liquid-like nuclear condensates.
• Liquid-liquid phase separation is identified as a mechanism for compartmentalizing active transcription regulated by PGC-1α in skeletal muscle.

Conclusions:

• PGC-1α utilizes RNA-binding and complex assembly to regulate transcription.
• Nuclear condensates and liquid-liquid phase separation are crucial for PGC-1α's function in adaptive transcription.
• This study provides a framework for understanding transcriptional control in metabolic adaptation.