The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control

Abstract

Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Keywords: BAF60a; BAF60b; BAF60c; SWI/SNF; chromatin-remodeling; energy metabolism; glucose; lipid; liver; nutrient sensing; skeletal muscle.

Figure 1

Metabolic regulation by BAF60a in liver. Hepatic BAF60a senses and integrates the environmental factors, such as starvation, circadian clock, and dietary fat consumption, to transcriptional reprogramming and metabolic adaptations, through its direct interaction with specific transcriptional factors/cofactors and SWI/SNF-mediated chromatin remodeling

Figure 2

Metabolic regulation by BAF60c in skeletal muscle. BAF60c drives glycolytic muscle metabolism through Deptor-mediated AKT activation. Mechanistically, BAF60c forms a transcriptional complex with Six4 and recruits the SWI/SNF complex to the proximal Deptor promoter to induce Deptor gene expression. This pathway is important for muscle glucose metabolism and whole body glucose homeostasis in both physiological and diabetic states. In severe diabetic condition, expression of BAF60c and Deptor is downregulated due to activation of ERK pathway by meta-inflammation. Rescue of this pathway by either treatment with an ERK inhibitor or transgenic expression of BAF60c in skeletal muscle ameliorates insulin resistance and improves whole body glucose homeostasis in HFD-induced or genetically obese mice. Under physiological condition, BAF60c acts as a glucose sensor in skeletal muscle. Glucose triggers K_ATP channel-dependent Ca²⁺ response, which elicits the phosphorylation and nuclear exclusion of HDAC5 downstream of CaMKII activation, resulting in BAF60c and Deptor induction and insulin-independent AKT activation. This glucose sensing pathway works in concert with insulin signaling pathway to maintain postprandial glucose homeostasis

Figure 3

Regulation of insulin-induced lipogenesis by BAF60c in mouse liver. Upon insulin treatment, BAF60c is phosphorylated and translocated to the nucleus, which leads to its direct interaction with phosphorylated/ acetylated USF-1, allowing the recruitment of SWI/SNF chromatin-remodeling complex and transcriptional induction of lipogenic genes