Role of Jhdm2a in regulating metabolic gene expression and obesity resistance

Abstract

Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases1,2. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development3,4. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts β-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by β-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor α (Ppara) and Ucp1 expression. Furthermore, we demonstrate that β-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Pparγ and Rxrα and their co-activators Pgc1aα(also known as Ppargc1a), CBP/ p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.

PPARs and adipocyte function

“…As expected PPAR expression was reduced in JHDM2A knockout BAT and coldinduced PPAR (and UCP1) induction was defective in these animals which displayed obesity (with normal caloric intake) and defective adaptive thermogenesis [57].…”

“…Notably, members of the steroid receptor co-activator (SRC) family of transcriptional regulators influence brown fat development and function by modulating the interaction of PPAR with PGC1 [56]. Additionally, the lysine 9 of histone H3 (H3K9)-specific demethylase JMJC domain-containing histone demethylase 2A (JHDM2A) was recently shown to contribute to -adrenergic-mediated UCP1 activation in BAT by augmenting recruitment of PPAR , RXR and PGC1 (along with SRC1 and p300) to the PPRE of the UCP1 enhancer [57]. Correspondingly, JHDM2A knockout mice displayed defective adaptive thermogenesis and cold-induced UCP1 induction was completely blocked in the BAT of…”

“…In these studies PGC1 and CREB-binding protein (CBP) synergistically co-activated PPAR transcriptional activity [96]. In parallel PPAR expression (and its nuclear translocation) was induced by cold exposure in rodent BAT [57,97]. This effect is likely to be mediated (at least in part) by the H3K9-specific demethylase JHDM2A.…”

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

“…Moreover, a recent report has implicated disorganization of heterochromatin at the lamina as a driver of human aging (Zhang et al., 2015). Numerous enzymes associated with H3K9me3, the mark associated with heterochromatin, including acetyltransferases (SRC‐1/ Ncoa1 ), deacetylases (Hdac3), methyltransferases (Suv39 h1 and G9a/ Ehmt2 ), and demethylases (Jhmdh2a/Kdm3a, Jmjd2c/Kdm4c), have been linked to fatty liver, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi et al., 2009; Wang et al., 2013). In addition, levels of H3K9me3 increase during caloric restriction and decrease in db/db mice and other models of hyperglycemia (Vaquero & Reinberg, 2009; Villeneuve et al., 2008).…”

“…Additionally, LMNA mutations lead to partial lipodystrophy, a condition associated with insulin‐resistant diabetes, hypertriglyceridemia, and hepatic steatosis (Shackleton et al., 2000). Multiple enzymes modulating covalent modifications to lysine 9 of histone 3 (H3K9), the mark associated with heterochromatin in lamina‐associated domains (Guelen et al., 2008), have been linked to fatty liver, hyperlipidemia, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi, Okada, Kallin & Zhang, 2009; Villeneuve et al., 2008; Wang et al., 2013). We have recently implicated lamina‐associated factors Hdac3 and Srf in age‐dependent dysregulation of lipid metabolism in the liver (Bochkis, Przybylski, Chen & Regev, 2014).…”