期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2105951118
关键词
gene transcription; transcriptional coactivator; chromatin; liquid-liquid phase separation; RNA-binding protein
资金
- Novartis Foundation for Medical-Biological Research
- Research Fund of the University of Basel
- Swiss National Science Foundation
- European Research Council Consolidator Grant [616830-MUSCLE_NET]
- Swiss Cancer Research Grant [KFS-3733-08-2015]
- Swiss Society for Research on Muscle Diseases, SystemsX.ch
- Novartis Stiftung fur Medizinisch-Biologische Forschung
- University of Basel
- Danish Diabetes Academy - Novo Nordisk Foundation [NNF17SA0031406]
This research has revealed the central role of the C-terminal domain of PGC-1 alpha in transcriptional regulation, showing its function in assembling multiprotein complexes to control gene transcription and RNA processing in liquid-like nuclear condensates. The compartmentalization of active transcription mediated by liquid-liquid phase separation in skeletal muscle provides insight into how PGC1 alpha regulates complex transcriptional networks, offering a broad conceptual framework for context-dependent transcriptional control of phenotypic adaptations in metabolically active tissues.
Plasticity of cells, tissues, and organs is controlled by the coordinated transcription of biological programs. However, the mechanisms orchestrating such context-specific transcriptional networks mediated by the dynamic interplay of transcription factors and coregulators are poorly understood. The peroxisome proliferator- activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a prototypical master regulator of adaptive transcription in various cell types. We now uncovered a central function of the C-terminal domain of PGC-1 alpha to bind RNAs and assemble multiprotein complexes including proteins that control gene transcription and RNA processing. These interactions are important for PGC-1 alpha recruitment to chromatin in transcriptionally active liquid-like nuclear condensates. Notably, such a compartmentalization of active transcription mediated by liquid-liquid phase separation was observed in mouse and human skeletal muscle, revealing a mechanism by which PGC1 alpha regulates complex transcriptional networks. These findings provide a broad conceptual framework for context-dependent transcriptional control of phenotypic adaptations in metabolically active tissues.
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