Publications (19) View all
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Article: Silencing of Lipid Metabolism Genes through IRE1α-Mediated mRNA Decay Lowers Plasma Lipids in Mice.
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ABSTRACT: XBP1 is a key regulator of the unfolded protein response (UPR), which is involved in a wide range of physiological and pathological processes. XBP1 ablation in liver causes profound hypolipidemia in mice, highlighting its critical role in lipid metabolism. XBP1 deficiency triggers feedback activation of its upstream enzyme IRE1α, instigating regulated IRE1-dependent decay (RIDD) of cytosolic mRNAs. Here, we identify RIDD as a crucial control mechanism of lipid homeostasis. Suppression of RIDD by RNA interference or genetic ablation of IRE1α reversed hypolipidemia in XBP1-deficient mice. Comprehensive microarray analysis of XBP1 and/or IRE1α-deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1α. Ablation of XBP1 ameliorated hepatosteatosis, liver damage, and hypercholesterolemia in dyslipidemic animal models, suggesting that direct targeting of either IRE1α or XBP1 might be a feasible strategy to treat dyslipidemias.Cell metabolism 10/2012; 16(4):487-99. · 17.35 Impact Factor -
Article: Interaction of Ets-1 with HDAC1 represses IL-10 expression in Th1 cells.
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ABSTRACT: IL-10 is a multifunctional cytokine that plays a crucial role in immunity and tolerance. IL-10 is produced by diverse immune cell types, including B cells and subsets of T cells. Although Th1 produce IL-10, their expression levels are much lower than Th2 cells under conventional stimulation conditions. The potential role of E26 transformation-specific 1 (Ets-1) transcription factor as a negative regulator for Il10 gene expression in CD4(+) T cells has been implicated previously. In this study, we investigated the underlying mechanism of Ets-1-mediated Il10 gene repression in Th1 cells. Compared with wild type Th1 cells, Ets-1 knockout Th1 cells expressed a significantly higher level of IL-10, which is comparable with that of wild type Th2 cells. Upregulation of IL-10 expression in Ets-1 knockout Th1 cells was accompanied by enhanced chromatin accessibility and increased recruitment of histone H3 acetylation at the Il10 regulatory regions. Reciprocally, Ets-1 deficiency significantly decreased histone deacetylase 1 (HDAC1) enrichment at the Il10 regulatory regions. Treatment with trichostatin A, an inhibitor of HDAC family, significantly increased Il10 gene expression by increasing histone H3 acetylation recruitment. We further demonstrated a physical interaction between Ets-1 and HDAC1. Coexpression of Ets-1 with HDAC1 synergistically repressed IL-10 transcription activity. In summary, our data suggest that an interaction of Ets-1 with HDAC1 represses the Il10 gene expression in Th1 cells.The Journal of Immunology 03/2012; 188(5):2244-53. · 5.79 Impact Factor -
Article: IRE1α activation protects mice against acetaminophen-induced hepatotoxicity.
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ABSTRACT: The mammalian stress sensor IRE1α plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1α can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1α in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1α activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1α suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1α-deficient mouse liver, indicating the essential role of IRE1α in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism.Journal of Experimental Medicine 02/2012; 209(2):307-18. · 13.85 Impact Factor -
Article: Looping mediated interaction between the promoter and 3' UTR regulates type II collagen expression in chondrocytes.
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ABSTRACT: Type II collagen is the major component of articular cartilage and is mainly synthesized by chondrocytes. Repeated sub-culturing of primary chondrocytes leads to reduction of type II collagen gene (Col2a1) expression, which mimics the process of chondrocyte dedifferentiation. Although the functional importance of Col2a1 expression has been extensively investigated, mechanism of transcriptional regulation during chondrocyte dedifferentiation is still unclear. In this study, we have investigated the crosstalk between cis-acting DNA element and transcription factor on Col2a1 expression in primary chondrocytes. Bioinformatic analysis revealed the potential regulatory regions in the Col2a1 genomic locus. Among them, promoter and 3' untranslated region (UTR) showed highly accessible chromatin architecture with enriched recruitment of active chromatin markers in primary chondrocytes. 3' UTR has a potent enhancer function which recruits Lef1 (Lymphoid enhancer binding factor 1) transcription factor, leading to juxtaposition of the 3' UTR with the promoter through gene looping resulting in up-regulation of Col2a1 gene transcription. Knock-down of endogenous Lef1 level significantly reduced the gene looping and subsequently down-regulated Col2a1 expression. However, these regulatory loci become inaccessible due to condensed chromatin architecture as chondrocytes dedifferentiate which was accompanied by a reduction of gene looping and down-regulation of Col2a1 expression. Our results indicate that Lef1 mediated looping between promoter and 3' UTR under the permissive chromatin architecture upregulates Col2a1 expression in primary chondrocytes.PLoS ONE 01/2012; 7(7):e40828. · 4.09 Impact Factor -
Article: IRF4 regulates IL-10 gene expression in CD4(+) T cells through differential nuclear translocation.
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ABSTRACT: CD4(+) T cells play critical roles in the generation of protective immunity against a variety of pathogens. The main two types of effector CD4(+) T cells, Th1 and Th2 are characterized by their ability to produce signature cytokines. Among them, IL-10 is a multi-functional cytokine that plays a crucial role in maintaining the balance between immunity and tolerance. Although IL-10 is produced by both differentiated primary Th1 and Th2 cells, Th2 cells produce much higher levels of IL-10 upon stimulation. However, little information is available on the molecular mechanisms of IL-10 gene regulation at the transcriptional level. Interferon regulatory factor IRF4 is a member of the IRF family of transcription factors and plays critical roles in the development of CD4(+) T cells into Th2 cells. In this present study, we elucidate the underlying mechanism of IRF4 mediated IL-10 gene transcription in primary CD4(+) T cells. Th2 specific binding of IRF4 to the IRF4 responsive elements in IL-10 locus potentiated IL-10 expression in Th2 cells. Knockdown of IRF4 by siRNA decreased IL-10 expression level in Th2 cells. Nuclear translocation of IRF4 was much higher in Th2 cells upon stimulation, which contribute to maintain IL-10(high) phenotype of Th2 cells. Collectively, our results suggest that stimulation driven quantitative differences of IRF4 in the nucleus and its binding to IL-10 regulatory elements are crucial mechanisms to induce IL-10(high) gene expression in Th2 cells.Cellular Immunology 03/2011; 268(2):97-104. · 1.97 Impact Factor
