Higher-Order Chromatin Regulation and Differential Gene Expression in the Human Tumor Necrosis Factor/Lymphotoxin Locus in Hepatocellular Carcinoma Cells

Watanabe, Takehisa; Ishihara, Kazuhíko; Hirosue, Akiyuki; Watanabe, Sugiko; Hino, Shinjiro; Ojima, Hidenori; Kanai, Yae; Sasaki, Yutaka; Nakao, Mitsuyoshi

doi:10.1128/mcb.06478-11

Cited by 28 publications

(26 citation statements)

References 75 publications

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“…42 Regulation of TNF expression by Ctcf is in agreement with the literature. 43 Additionally, we show diminished IL-10 production by macrophages as a result of Ctcf depletion, similarly to low IL-10 production upon Ctcf deletion in Th2 cells as we previously observed. 19 In macrophages, TLR4 stimulation induces IL-10 production through TRAF3 and NF-kB 26,44 and-indeed-we found downregulation of genes downstream of the NF-kB complex in LysM-Cre Ctcf f/f macrophages.…”

Section: Discussionsupporting

confidence: 87%

The DNA-binding factor Ctcf critically controls gene expression in macrophages

et al. 2013

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Section: Discussionsupporting

confidence: 87%

The DNA-binding factor Ctcf critically controls gene expression in macrophages

et al. 2013

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“…Antigen retrieval was carried out by heating in a target retrieval solution (Tris/EDTA buffer, pH 9; Dako Cytomation) for GLUT1 and in a 0.01 mol/L citrate buffer (pH 6.0) for LSD1 at 121 C for 10 minutes in a pressure cooker. The other procedures used in IHC were similar to our previous report (22).…”

Section: Immunohistochemistrymentioning

confidence: 91%

“…As described previously (22), histologic classification was assessed according to the World Health Organization Histological Classification of Tumors. The Ethics Committee of the National Cancer Center approved this study, with written informed consent from all patients.…”

Section: Patients and Histologic Assessmentmentioning

confidence: 99%

Lysine Demethylase LSD1 Coordinates Glycolytic and Mitochondrial Metabolism in Hepatocellular Carcinoma Cells

et al. 2015

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The hallmark of most cancer cells is the metabolic shift from mitochondrial to glycolytic metabolism for adapting to the surrounding environment. Although epigenetic modification is intimately linked to cancer, the molecular mechanism, by which epigenetic factors regulate cancer metabolism, is poorly understood. Here, we show that lysine-specific demethylase-1 (LSD1, KDM1A) has an essential role in maintaining the metabolic shift in human hepatocellular carcinoma cells. Inhibition of LSD1 reduced glucose uptake and glycolytic activity, with a concurrent activation of mitochondrial respiration. These metabolic changes coexisted with the inactivation of the hypoxia-inducible factor HIF1a, resulting in a decreased expression of GLUT1 and glycolytic enzymes. In contrast, during LSD1 inhibition, a set of mitochondrial metabolism genes was activated with the concomitant increase of methylated histone H3 at lysine 4 in the promoter regions. Consistently, both LSD1 and GLUT1 were significantly overexpressed in carcinoma tissues. These findings demonstrate the epigenetic plasticity of cancer cell metabolism, which involves an LSD1-mediated mechanism.

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“…This study also found that CTCF binds to LTB exon 4, indicating that CTCF may contribute to the formation of a repressive loop structure (Wicks & Knight, 2011). By contrast, another study in hepatocellular carcinoma cells implicated the formation of an enhancer-containing chromosomal loop, dependent upon CTCF and the cohesin RAD21, in the activation of LTB transcription (Watanabe et al, 2012). CTCF/RAD21 binding sites were characterized within LTB exon 4 (the site being designated TC3), upstream of and within the NFKBIL1 gene (TC1 and TC2, which lie 29.5 and 34.2 kb from TC3, respectively), and upstream of the LST1 gene (TC4, which lies 4.7 kb from TC3; Fig.…”

Section: Cytokine Gene Regulationmentioning

confidence: 98%

“…In the early phase of gene expression following TNF stimulation in these cells, in which expression of both TNF and LTB is favored, TC1–TC4 are physically associated with the TNF , LTA , and LTB promoters and with an NF-κB-dependent enhancer region, TE2, in the 3′-UTR of TNF . By contrast, in the late phase of gene expression, in which LTB transcription is favored, TC3, TE2, and the LTB promoter remain associated, as do TC2 and the TNF and LTA promoters (Watanabe et al, 2012; Fig. 2.2A).…”

Section: Cytokine Gene Regulationmentioning

confidence: 99%

Epigenetic Control of Cytokine Gene Expression

Falvo

Jasenosky

Kruidenier

et al. 2013

Advances in Immunology

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Epigenetics encompasses transient and heritable modifications to DNA and nucleosomes in the native chromatin context. For example, enzymatic addition of chemical moieties to the N-terminal “tails” of histones, particularly acetylation and methylation of lysine residues in the histone tails of H3 and H4, plays a key role in regulation of gene transcription. The modified histones, which are physically associated with gene regulatory regions that typically occur within conserved noncoding sequences, play a functional role in active, poised, or repressed gene transcription. The “histone code” defined by these modifications, along with the chromatin-binding acetylases, deacetylases, methylases, demethylases, and other enzymes that direct modifications resulting in specific patterns of histone modification, shows considerable evolutionary conservation from yeast to humans. Direct modifications at the DNA level, such as cytosine methylation at CpG motifs that represses promoter activity, are another highly conserved epigenetic mechanism of gene regulation. Furthermore, epigenetic modifications at the nucleosome or DNA level can also be coupled with higher-order intra- or interchromosomal interactions that influence the location of regulatory elements and that can place them in an environment of specific nucleoprotein complexes associated with transcription. In the mammalian immune system, epigenetic gene regulation is a crucial mechanism for a range of physiological processes, including the innate host immune response to pathogens and T cell differentiation driven by specific patterns of cytokine gene expression. Here, we will review current findings regarding epigenetic regulation of cytokine genes important in innate and/or adaptive immune responses, with a special focus upon the tumor necrosis factor/lymphotoxin locus and cytokine-driven CD4+ T cell differentiation into the Th1, Th2, and Th17 lineages.

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Higher-Order Chromatin Regulation and Differential Gene Expression in the Human Tumor Necrosis Factor/Lymphotoxin Locus in Hepatocellular Carcinoma Cells

Cited by 28 publications

References 75 publications

The DNA-binding factor Ctcf critically controls gene expression in macrophages

The DNA-binding factor Ctcf critically controls gene expression in macrophages

Lysine Demethylase LSD1 Coordinates Glycolytic and Mitochondrial Metabolism in Hepatocellular Carcinoma Cells

Epigenetic Control of Cytokine Gene Expression

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