Publications by authors named "Tie Zou"

11 Publications

  • Page 1 of 1

Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity.

Dev Cell 2015 Dec 25;35(5):568-583. Epub 2015 Nov 25.

Department of Molecular, Cell and Cancer Biology and Program in Molecular Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address:

Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3 and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes. Jmjd3-catalyzed removal of H3K27me3, in part through Rreb1-mediated recruitment, is required for expression of BAT-selective genes and for development of beige adipocytes both in vitro and in vivo. Moreover, gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight reduction and cold intolerance, respectively. Together, we identify an epigenetic mechanism governing BAT fate determination and WAT plasticity.
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http://dx.doi.org/10.1016/j.devcel.2015.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679478PMC
December 2015

Multiple redundant effector mechanisms of CD8+ T cells protect against influenza infection.

J Immunol 2013 Jan 28;190(1):296-306. Epub 2012 Nov 28.

Trudeau Institute, Saranac Lake, NY 12983, USA.

We have previously shown that mice challenged with a lethal dose of A/Puerto Rico/8/34-OVA(I) are protected by injection of 4-8 × 10(6) in vitro-generated Tc1 or Tc17 CD8(+) effectors. Viral load, lung damage, and loss of lung function are all reduced after transfer. Weight loss is reduced and survival increased. We sought in this study to define the mechanism of this protection. CD8(+) effectors exhibit multiple effector activities, perforin-, Fas ligand-, and TRAIL-mediated cytotoxicity, and secretion of multiple cytokines (IL-2, IL-4, IL-5, IL-9, IL-10, IL-17, IL-21, IL-22, IFN-γ, and TNF) and chemokines (CCL3, CCL4, CCL5, CXCL9, and CXCL10). Transfer of CD8(+) effectors into recipients, before infection, elicits enhanced recruitment of host neutrophils, NK cells, macrophages, and B cells. All of these events have the potential to protect against viral infections. Removal of any one, however, of these potential mechanisms was without effect on protection. Even the simultaneous removal of host T cells, host B cells, and host neutrophils combined with the elimination of perforin-mediated lytic mechanisms in the donor cells failed to reduce their ability to protect. We conclude that CD8(+) effector T cells can protect against the lethal effects of viral infection by means of a large number of redundant mechanisms.
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http://dx.doi.org/10.4049/jimmunol.1200571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864858PMC
January 2013

The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

PLoS Genet 2012 14;8(6):e1002761. Epub 2012 Jun 14.

Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.
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http://dx.doi.org/10.1371/journal.pgen.1002761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375226PMC
September 2012

Listeria monocytogenes infection induces prosurvival metabolic signaling in macrophages.

Infect Immun 2011 Apr 24;79(4):1526-35. Epub 2011 Jan 24.

Program in Gene Function and Expression and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Host cells use metabolic signaling through the LXRα nuclear receptor to defend against Listeria monocytogenes infection. 25-Hydroxycholesterol is a natural ligand of LXRs that is produced by the enzyme cholesterol 25-hydroxylase (CH25H). We found that expression of Ch25h is upregulated following L. monocytogenes infection in a beta interferon (IFN-β)-dependent fashion. Moreover, increased Ch25h expression promotes survival of L. monocytogenes-infected cells and increases sensitivity of the host to infection. We determined that expression of Cd5l, a prosurvival gene, is controlled by CH25H. In addition, we found that CD5L inhibits activation of caspase-1, promoting survival of infected macrophages. Our results reveal a mechanism by which an intracellular pathogen can prolong survival of infected cells, thus providing itself with a protected environment in which to replicate.
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http://dx.doi.org/10.1128/IAI.01195-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067555PMC
April 2011

SMN deficiency reduces cellular ability to form stress granules, sensitizing cells to stress.

Cell Mol Neurobiol 2011 May 15;31(4):541-50. Epub 2011 Jan 15.

Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that is caused by deletion of the SMN (Survival of Motor Neuron) gene. The SMN protein is essential for cell survival and co-localized with TIA-1/R and G3BP, two characteristic markers of stress granules (SGs). To further study the SMN function in stress granules and in response to stress, we generated stable cell lines with SMN knockdown. Our data indicate that suppression of SMN drastically reduces cellular ability to form stress granules in response to stress treatment. In addition, we show that SMN deficiency sensitizes cells to sodium arsenite and H(2)O(2), two well-known stress inducers, leading to cell death at a much lower concentration of inducers in SMN knockdown cells than in control cells. Interestingly, the cell death is correlated with formation of stress granules, suggesting that involvement of SMN in formation of stress granules may play an important role in cell survival. Furthermore, rescue of SGs formation by overexpression of G3BP can reverse the defective formation of stress granules and results in partial abrogation of cell death against SMN deficiency. We deduce that modulation of stress response may be useful for potential SMN treatment.
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http://dx.doi.org/10.1007/s10571-011-9647-8DOI Listing
May 2011

Alternative splicing of exon 10 in the tau gene as a target for treatment of tauopathies.

BMC Neurosci 2008 Dec 3;9 Suppl 2:S10. Epub 2008 Dec 3.

Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies.
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http://dx.doi.org/10.1186/1471-2202-9-S2-S10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604894PMC
December 2008

Emetine regulates the alternative splicing of Bcl-x through a protein phosphatase 1-dependent mechanism.

Chem Biol 2007 Dec;14(12):1386-92

Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

Exon 2 of the Bcl-x gene undergoes alternative splicing in which the Bcl-xS splice variant promotes apoptosis in contrast to the anti-apoptotic splice variant Bcl-xL. In this study, the regulation of the alternative splicing of pre-mRNA of Bcl-x was examined in response to emetine. Treatment of different types of cancer cells with emetine dihydrochloride downregulated the level of Bcl-xL mRNA with a concomitant increase in the mRNA level of Bcl-xS in a dose- and time-dependent manner. Pretreatment with calyculin A, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), blocked emetine-induced alternative splicing in contrast to okadaic acid, a specific inhibitor of PP2A in cells, demonstrating a PP1-mediated mechanism. Our finding on the regulation of RNA splicing of members of the Bcl-2 family in response to emetine presents a potential target for cancer treatment.
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http://dx.doi.org/10.1016/j.chembiol.2007.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2186211PMC
December 2007

SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity.

Biochem Biophys Res Commun 2007 Dec 25;364(4):850-5. Epub 2007 Oct 25.

Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB 325, Worcester, MA 01605, USA.

Deletion or mutation of the survival of motor neuron (SMN1) gene causes Spinal Muscular Atrophy (SMA), a motor neuron degenerative disease. To study the SMN function, we co-transfected mouse NSC34 cells with SMN and mutant superoxide dismutase 1 (SOD1) constructs. We demonstrated that SMN protected NSC34 cells against cell death induced by mutant SOD1 under oxidative stress. Further studies indicated that over-expression of wild-type SMN up-regulated chaperone activity. In contrast, chaperone activity was decreased in cells expressing SMN mutant Y272C or in cells with SMN suppressed by shRNA. In vitro assays using bacteria lysates expressing GST-SMN or purified GST-SMN protein showed that the GST-SMN reduced catalase aggregation, indicating that SMN may possess chaperone activity. We conclude that SMN plays a protective role in motor neurons by its chaperone activity. Our results provide support for the potential development of therapy for SMA and amyotrophic lateral sclerosis (ALS).
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http://dx.doi.org/10.1016/j.bbrc.2007.10.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169267PMC
December 2007

Disruption of tissue-type plasminogen activator gene in mice aggravated liver fibrosis.

J Gastroenterol Hepatol 2008 Jul 17;23(7 Pt 2):e258-64. Epub 2007 Oct 17.

Department of Molecular Genetics, Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical School, Fudan University, Shanghai, China.

Background And Aim: Tissue-type plasminogen activator (tPA) is one of the major components in the matrix proteolytic network whose role in the pathogenesis of liver fibrosis remains unknown. The aim of this study is to investigate the role of tPA in carbon tetrachloride (CCl(4))-induced liver fibrosis.

Methods: Wild-type and tPA knockout mice (8 mice per group) were injected interperitoneumly with 25% CCl(4) 2 ml/kg twice per week as CCl(4) administration groups and olive oil 2 ml/kg as controls. After 4 weeks, the livers of mice were removed under deep anesthesia and prepared for further studies such as histology, immunostaining, hydroxyproline assay, zymography and western blot analysis.

Results: Mice lacking tPA developed more severe morphological injury and displayed an increased deposition of collagen in the liver after CCl(4) administration compared with wild-type counterparts. Deficiency of tPA increased alpha-smooth muscle actin expression in the mice livers. On the other hand, the decrease of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) activities, metalloproteinase-13 (MMP-13) expression and a marked increase of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression were found in the liver of CCl(4) administrated tPA(-/-) mice compared with wild-type counterparts.

Conclusions: Deficiency of tPA aggravated liver fibrosis through promoting hepatic stellate cells (HSCs) activation and inhibiting ECM degradation by decreasing MMP-2, MMP-9 activities and disrupting the balance between MMP-13 and TIMP-1.
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http://dx.doi.org/10.1111/j.1440-1746.2007.05100.xDOI Listing
July 2008

Disruption of tissue plasminogen activator gene reduces macrophage migration.

Biochem Biophys Res Commun 2006 Oct 28;349(3):906-12. Epub 2006 Aug 28.

Department of Molecular Genetics and the Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai 200032, PR China.

Tissue plasminogen activator (tPA) is an essential component of the proteolytic cascade that lyses blood clots. Various studies also suggest that tPA plays important roles in peripheral nerve regeneration. Here we show that disruption of tPA gene reduces macrophage migration after sciatic nerve injury in mice. Moreover, lack of tPA activity attenuates migrating ability of macrophages and affects MMP-9 expression and activity in macrophages in vitro. Addition of ethylenediaminetetraacetic acid (EDTA), which inhibits MMPs, abolished the differences of migration ability of macrophages between tPA(+/+) and tPA(-/-) mice. Axonal regeneration is correlated with the increase of macrophage migration, suggesting that tPA may help create a beneficial environment for axonal regeneration through promoting macrophage infiltration. This study shows that tPA may play a role in nerve regeneration through regulating the migration ability of macrophages. This function of tPA may depend on, at least in part, upregulating MMP-9 expression and activity in macrophages.
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http://dx.doi.org/10.1016/j.bbrc.2006.08.111DOI Listing
October 2006

Exogenous tissue plasminogen activator enhances peripheral nerve regeneration and functional recovery after injury in mice.

J Neuropathol Exp Neurol 2006 Jan;65(1):78-86

Department of Molecular Genetics & the Key Laboratory of Molecular Medicine Ministry of Education, Fudan University, Shanghai, P.R. China.

Tissue plasminogen activator (tPA) is an essential component of the proteolytic cascade that lyses blood clots. Various studies also suggest that tPA plays important roles in the nervous system. We show that exogenous tPA or tPA/plasminogen (plg) promotes axonal regeneration, remyelination, and functional recovery after sciatic nerve injury in the mouse. Local application of tPA or tPA/plg 7 days after sciatic nerve crush significantly increased the total number of axons and myelinated axons, which is accompanied by enhanced expression of neurofilament. Treatment with tPA or tPA/plg reduced the deposition of fibrin(ogen) after nerve injury. Moreover, tPA or tPA/plg increased the number of macrophages and induced MMP-9 expression at the injury site, coincident with reduced collagen scar formation and accelerated clearance of myelin and lipid debris after treatment. Consequently, tPA or tPA/plg treatment protected muscles from atrophy after nerve injury, indicating better functional recovery. These results suggest that administration of exogenous tPA or tPA/plg promotes axonal regeneration and remyelination through removal of fibrin deposition and activation of MMP-9-positive macrophages, which may be responsible for myelin debris clearance and preventing collagen scar formation. Therefore, tPA may be useful for treatment of peripheral nerve injury.
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http://dx.doi.org/10.1097/01.jnen.0000195942.25163.f5DOI Listing
January 2006