JAZF1: A metabolic actor subunit of the NuA4/TIP60 chromatin modifying complex

Abstract

The multisubunit NuA4/TIP60 complex is a lysine acetyltransferase, chromatin modifying factor and gene co-activator involved in diverse biological processes. The past decade has seen a growing appreciation for its role as a metabolic effector and modulator. However, molecular insights are scarce and often contradictory, underscoring the need for further mechanistic investigation. A particularly exciting route emerged with the recent identification of a novel subunit, JAZF1, which has been extensively linked to metabolic homeostasis. This review summarizes the major findings implicating NuA4/TIP60 in metabolism, especially in light of JAZF1 as part of the complex.

Keywords: acetyl-CoA; acetylation; epigenetics; gene expression; lipogenesis; lipolysis.

FIGURE 1

KATs at the nexus of crosstalk between chromatin modification and metabolism. Glucose and fatty acids constitute the main source of cytoplasmic acetyl-CoA, where pyruvate (product of glycolysis) and fatty acids enter the mitochondria to produce acetyl-CoA which feeds into the tricarboxylic acid (TCA) cycle and produces citrate. Citrate is then transported to the cytoplasm where it can yield acetyl-CoA. Other sources include acetate or direct conversion of cytoplasmic pyruvate into acetyl-CoA. The pool of acetyl-CoA available for KAT activity is sensitive to fluctuations in nutrient availability, activity of the metabolic enzymes that catalyze acetyl-CoA production, and the metabolic signaling cascades modulating metabolic enzymes. KATs can therefore communicate the metabolic state of the cell to chromatin and correspondingly adjust the transcriptional output, including that of metabolic genes. KATs themselves are involved in metabolic signaling as they are known to directly modify and regulate metabolic enzymes.

FIGURE 2

JAZF1 fine-tunes metabolic activity of the NuA4/TIP60 complex. Hypothetical model for the role of JAZF1 within the NuA4/TIP60 complex. (A) Enzymatic activity and specificity of the NuA4/TIP60 complex, either on chromatin at metabolic genes or towards metabolic enzymes, may be sensitive to the presence or absence of JAZF1 in the complex, which in turn could be controlled by expression, subcellular localization, or context-dependent assembly into the complex. Based on homology with Sfp1, mTOR-mediated phosphorylation may be involved in the process. (B) JAZF1 is possibly required for NR2C2-dependent recruitment of the NuA4/TIP60 complex at specific gene targets.