Chromatin-remodeling links metabolic signaling to gene expression

Abstract

Background: ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.

Scope of review: This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.

Major conclusions: INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.

Keywords: BAF/PBAF; Chromatin-remodeling; INO80; Metabolism; SWI/SNF; TOR.

Figure 1

Respiration and gene oscillations in the yeast metabolic cycle (YMC). Metabolically, synchronization is facilitated by growing cells to saturation followed by continuous batch feeding of the culture with low glucose media in a closed bioreactor environment. The YMC is divided into three phases depending on respiration as monitored by dissolved oxygen (DO) in the culture. mRNA expression plots are shown as determined from reference [36]. n = number of genes previously determined to undergo periodic gene expression [36].

Figure 2

INO80 complex is a component of the TOR signaling pathway that regulates metabolic gene expression. The model illustrates the INO80 complex at promoters targeted by Msn2/4, Tod6, and Dot6 that are phosphorylated in the TORC1 signaling pathway and regulate ribosome biogenesis, nitrogen metabolism, and stress responses. The INO80 complex is a model of the electron microscopy-derived structure bound to a nucleosome (PDB and 6FML) [84]. DNA is shown in green and the INO80-bound nucleosome in red. The INO80 complex regulates promoter accessibility and histone acetylation at target genes. TORC1 signaling regulates Msn2/4 subcellular localization and Tod6/Dot6 chromatin recruitment.