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  • Many histone modifying enzymes play crucial

    2019-07-30

    Many histone-modifying enzymes play crucial roles in metabolic diseases, including insulin resistance, obesity and diabetes. For examples, SIRT1, a NAD+-dependent histone deacetylase, is downregulated in insulin-resistant Ethylmalonyl Coenzyme A and tissues [13]; hepatic SIRT1 deficiency impairs mTorc2/Akt signaling, causing hyperglycemia and insulin resistance in mice [14]. Meanwhile, hepatic knockout of a NAD+-independent histone deacetylase, HDAC3, causes lipid accumulation and glycogen depletion in mouse liver [15]. Furthermore, liver-specific overexpression of HDAC3 promotes gluconeogenesis through suppressing lipid synthesis and sequestration [16]. In addition to histone acetylation regulating enzymes, the role of histone methylation regulating enzymes in metabolic diseases also caught great attentions. For example, Jhdm2a, a H3K9 specific demethylase, directly regulates the expression of peroxisome proliferator-activated receptor α (PPARα) [17], the key factor regulating lipid metabolism [18], [19]; loss of Jhdm2a leads to obesity and hyperlipidemia in rodents [17]. However, the roles of other histone-modifying enzymes in metabolic diseases remain elusive. Previously, we reported that under continuous high-fat diets (HFD), the male offspring mice gradually develop severe metabolic syndromes, including obesity, insulin resistance and diabetes over successive generations [20]. This phenomenon is associated with gradual downregulations of histone methylation level and histone methyltransferase G9a/EHMT2 in the liver over generations [20], indicating a previously unappreciated link between G9a and metabolic diseases. Among histone lysine methyltransferases (HKMTs), G9a and GLP (G9a-like protein)/EHMT1 are two primary enzymes responsible for mono- and di-methylation at Lys9 of histone H3 (H3K9me1 and H3K9me2). G9a and GLP predominantly co-exist in a heteromeric complex, in which G9a is essential for the function of methyltransferase and stability of the complex [21]. Here, by investigating its role in regulating insulin signaling and HMGA1 expression, we suggest G9a is a potential therapeutic target for hepatic insulin resistance.
    Materials and methods
    Results
    Discussion Since G9a is expressed ubiquitously and functions as a major euchromatic H3K9me1 and H3K9me2 HKMT, its broad biological roles such as in embryo development, muscle differentiation, tumor cell growth and immune response, have been proposed [33], [34]. However, the roles of G9a in metabolic regulation, especially on insulin resistance and glucose homeostasis, remain poorly understood. Here, we show that G9a regulates the expression of insulin receptor, which suggests a novel regulatory network between G9a and insulin signaling. We further provide evidence that G9a improves insulin signaling via positive regulation of HMGA1, an architectural transcription factor responsible for regulating insulin receptor gene INSR [10]. Finally, we demonstrate that G9a is required to restore insulin signaling in db/db mice by increasing HMGA1 and insulin receptor levels. Together, our study uncovers a new regulatory role for G9a in the expression of insulin receptor, and provides a mechanistic explanation for G9a in insulin signaling depending on its regulatory role on HMGA1 expression, at least in part. Hepatic insulin signaling plays an essential role in the regulation of glucose and lipid metabolism [35]. Through hepatic insulin signaling, insulin not only promotes the glucose transportation from blood into the liver and its subsequent conversion into glycogen for energy storage, but also enhances hepatic glycolysis and inhibits gluconeogenesis [36]. Deficiency in hepatic insulin signaling, especially knockdown of insulin receptor, leads to insulin resistance and metabolic disorders. Insulin receptor is essential for initiating downstream insulin signaling cascades [37], [38], [39]. It has been reported that a nucleoprotein complex, consisting of HMGA1, C/EBPβ and Sp1, regulates the transcription of INSR [9]. In addition, an adapter protein Grb10 (growth factor receptor-bound protein 10), positively regulates the protein level of insulin receptor by enhancing stability and reducing its ubiquitination [40]. Here we identified G9a as a new regulator for insulin receptor expression and subsequent insulin signaling in vitro and in vivo.