Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis

Area of Science:

• Molecular Biology
• Epigenetics
• Cellular Differentiation

Background:

• Enhancer activation is crucial for cell-type specific gene expression.
• The transition of enhancers from a hypoacetylated to a hyperacetylated state during differentiation is not fully understood.

Purpose of the Study:

• To investigate the role of SET domain-containing 5 (SETD5) in regulating enhancer activity during adipogenesis.
• To elucidate the mechanism by which enhancers become active during the differentiation process.

Main Methods:

• Co-immunoprecipitation to identify protein complexes.
• Western blotting to assess protein levels.
• Chromatin immunoprecipitation followed by qPCR to analyze histone acetylation at specific gene enhancers.

Main Results:

• SETD5 forms a complex with NCoR-HDAC3, inhibiting enhancer acetylation for Cebpa and Pparg early in adipogenesis.
• SETD5 protein levels transiently increase and are rapidly degraded before enhancer activation.
• CDC20 induction leads to APC/C-mediated degradation of SETD5, triggering enhancer hyperacetylation.

Conclusions:

• SETD5 acts as a repressor of enhancer acetylation during adipogenesis.
• The degradation of SETD5 by the CDC20-APC/C pathway serves as a molecular switch for enhancer activation and adipogenesis.