Abstract
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.
Highlights
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood
In the current study, using protein interaction-based proteomics in the 3T3-L1 preadipocyte differentiation system, we identified SET domaincontaining 5 (SETD5) as a previously unappreciated component of the chromatin landscape that is required for adipocyte differentiation
Our studies show SETD5 interacts with the nuclear receptor co-repressors (NCoRs)–HDAC3 complex to maintain enhancers for master genes of adipocyte differentiation in a histone hypoacetylated but “primed state” that is inactive
Summary
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Motif analysis showed that class i regions had motifs enriched in C/EBP and PPAR-RXR binding sequences (Fig. 2c), suggesting that SETD5-containing NCoR-HDAC3 repressor complex inhibits H3K27 hyperacetylation of enhancers (i.e. active state) bound by these transcription factors.
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