MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat‐induced steatosis

Abstract

The importance of epigenetic changes in the development of hepatic steatosis is largely unknown. The histone variant macroH2A1 under alternative splicing gives rise to macroH2A1.1 and macroH2A1.2. In this study, we show that the macroH2A1 isoforms play an important role in the regulation of lipid accumulation in hepatocytes. Hepatoma cell line and immortalized human hepatocytes transiently transfected or knocked down with macroH2A1 isoforms were used as in vitro model of fat-induced steatosis. Gene expressions were analyzed by quantitative PCR array and Western blot. Chromatin immunoprecipitation analysis was performed to check the association of histone H3 lysine 27 trimethylation (H3K27me3) and histone H3 lysine 4 trimethylation (H3K4me3) with the promoter of lipogenic genes. Livers from knockout mice that are resistant to lipid deposition despite a high-fat diet were used for histopathology. We found that macroH2A1.2 is regulated by fat uptake and that its overexpression caused an increase in lipid uptake, triglycerides, and lipogenic genes compared with macroH2A1.1. This suggests that macroH2A1.2 is important for lipid uptake, whereas macroH2A1.1 was found to be protective. The result was supported by a high positivity for macroH2A1.1 in knockout mice for genes targeted by macroH2A1 (Atp5a1 and Fam73b), that under a high-fat diet presented minimal lipidosis. Moreover, macroH2A1 isoforms differentially regulate the expression of lipogenic genes by modulating the association of the active (H3K4me3) and repressive (H3K27me3) histone marks on their promoters. This study underlines the importance of the replacement of noncanonical histones in the regulation of genes involved in lipid metabolism in the progression of steatosis.

QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis

“…Similar to most macrodomains, macroH2A1.1's macrodomain can interact with NAD + -derived ligands, such as PAR, whereas the macrodomain of macroH2A1.2 cannot. This distinction is functionally important in cancer, in which reduction in macroH2A1.1 occurs in several tumor types and the alteration in macroH2A1.1 expression has important effects on both the proliferation and metastatic potential of cancer cells [18, 28]. In the present study, we demonstrated that macroH2A1.1 inhibited GC cell proliferation, migration, and invasion by repressing CCNL1 expression.…”

“…The macrodomain of macroH2A1.1 can interact with NAD + -derived small molecules, whereas macroH2A1.2's macrodomain cannot [14–16]. Current data from several groups have demonstrated that macroH2A1 plays important roles in both tumor suppression and differentiation, and the alteration in macroH2A1 splicing and expression occurs in a variety of cancers, including testicular, lung, urinary bladder, cervical, breast, colon, ovarian, and endometrial cancers [16–18]. However, the involvement of macroH2A1 splicing in gastric cancer (GC), the factors regulating the splicing of macroH2A1, and the biological role of macroH2A1 splicing are largely unknown in gastric carcinogenesis.…”

The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1

“…Moreover, while inhibiting p300-dependent histone acetylation in vitro (Doyen et al, 2006), mH2A1 has been recently reported to cooperate with PARP-1 to regulate transcription by promoting CBP-mediated acetylation of histone H2B at lysines 12 and 120, with opposing effects on transcription (Chen et al, 2014). These and other observations (Creppe et al, 2012) (Podrini et al, 2014) indicate that mH2A1 may exert a dual function in regulating gene expression.…”

Persistent Chromatin Modifications Induced by High Fat Diet*

“…Other persistently up-regulated genes of note are Fam73b and Acot11. Fam73 knock-out mice are lean and have increased macroH2A1.1 expression, a histone variant associated with regulation of lipogenic gene expression (38,39). Acot11 encodes an enzyme that catalyzes the hydrolysis of fatty acylCoAs, protecting against diet-induced obesity.…”