2017/03/09 Journal Club

The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory.

(PubMed連結)
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Yi-Chen slide 按我預覽或下載
Yi-Chen 補充說明slide 按我預覽或下載

2017/02/23 Journal Club paper

Succinate is an inflammatory signal that induces IL-1β through HIF-1α.

<PubMed連結>

Wei-Chanの slide <按我預覽或下載>

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2014/06/20  咦, 有PubPeer alert呦...
Christos Chinopoulos | Jun 20 2014 05:48 EST

Could it be that LPS-induced succinate over-production is due to itaconate formation? LPS induces Irg1, a gene coding for cis-aconitate decarboxylase, specifically expressed in cells of macrophage lineage Proc Natl Acad Sci U S A. 2013 May 7;110(19):7820-5. doi: 10.1073/pnas.1218599110, yielding itaconate.  Itaconate is preferentially used by succinyl CoA ligase forming itaconyl CoA, thus generating an accumulation of succinate when the ligase operates towards succinyl CoA formation ADLER J, WANG SF, & Lardy HA (1957) The metabolism of itaconic acid by liver mitochondria. J. Biol. Chem, 229, 865-879, and WANG SF, ADLER J, & Lardy HA (1961) The pathway of itaconate metabolism by liver mitochondria. J. Biol. Chem, 236, 26-30. http://www.ncbi.nlm.nih.gov/pubmed/23535595#cm23535595_4939

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2017/02/23 奕宏問了一個好問題, 抱歉, 我回來想想我當場的解釋並不正確, 現在重來一次! Orz...

Suppl Fig 15

奕宏問說, 既然IL1B是HIF1A(a transcription factor)的下游, 何以兩者的表現量未呈正相關?

我原先回答說transcript regulation level(IL1B)和protein regulation level (HIF1A)不同, 不用這樣子一起比。但是， 仔細看著它們， 既然細胞是一樣的， 不管受什麼level調節，兩者應該要同上同下才對，因為它們的context是相同的。

因此，剩下的唯一可能應是使用diethylsuccinate(DS)和butylmalonate(BM)所造成的差異。例如，BM除了induce HIF1A stabilization以外，還有stabilize其它IL1B之上游分子，而那些因子在DS那一組並未出現。如此便可解釋為何HIF1A和IL1B在兩種藥處理下，蛋白量並未成正相關。 How do you like this idea, Yi-Hong? 😀

2017/02/02 Journal Club paper

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer.

< PubMed 連結> PMID: 27713748

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奕宏報告的PPT檔 按我預覽或下載

奕宏補充報告PPT檔 按我預覽或下載

2017/1/12 Journal Club Paper

Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps.

PubMed 連結

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秀鈴 transformed the PPT file to two PDF because it's too huge to be attached.  Best, SL

PDF1 (按我預覽或下載)  PDF2 (按我預覽或下載)

The Schedule

Place: R2-3042; Time: 12:00-14:00; 30 min presentation + 30-40 min discussion

Please send the title and the PDF file of the paper being presented to all the members one week before the talk.
輪到你的時候，請在一周前把題目及pdf檔寄給大家謝謝。

For 奕宏 talk at "I Love Immunology" on 2/2

Dear 奕宏: 我覺得#4在講premalignant lesion和PGE2 (https://goo.gl/RjzJaX) 那篇不錯。

另外，這裡有作者簡介的新聞 PUBLIC RELEASE: 30-NOV-2016

I get by with help from my friends: Maintaining immune cells in head and neck cancer (https://goo.gl/FCs7Gg）

參加人員名單暫存區

黃麗蓉 Lab

鄭雲心 <cloudheard@gmail.com>, 

陳宥婕 <Emilyycchen@nhri.org.tw>,
黃麗蓉 < lrhuang@nhri.org.tw>,

蘇郁文 Lab

徐偉展 <weichanhsu@nhri.org.tw>,

陳明玉 <cmy6075@nhri.org.tw>, 

蘇郁文 <yuwensu@nhri.org.tw>,

許素菁 Lab

簡秀鈴 <sljian@nhri.org.tw>,

李宜珍 <ycli@nhri.org.tw>,
王復輝 <fhwang0919@gmail.com>,
莊雯婷 <chuangwenting@gmail.com>,

許素菁 <mschsu@nhri.org.tw>,

林素芳 Lab 

劉奕宏 <haloedition8@gmail.com>,

柯英潔 <ingridko0128@gmail.com>,

陳玉蓮 <lanie0407@gmail.com>,

林素芳 <sflin@nhri.org.tw>

17th Biennial EBV Meeting @ Switzerland (Aug/8-Aug/12)

有些abstract已被剪到GRC NPC個人檔案中

Monday, 2016/08/08 
Session 1: EBV epidemiology and sequence variation 2:30pm-
Chairpersons:
Henri-Jacques Delecluse, German Cancer Research Institute, Heidelberg, Germany

Alan Chiang, University of Hong Kong, China

1. Heterogeneity of the major internal repeat (IR1) of Epstein-Barr virus implicates interstrain recombination in pathogenesis, and includes a nonsense mutation of EBNA-LP in the prototype strain B95-8.
Mohammed Ba Abdullah, Imperial College London, UK
2. High levels of antibody that neutralize B-cell infection of Epstein-Barr virus and that bind EBV gp350 are associated with a lower risk of nasopharyngeal carcinoma
 Anna Coghill, National Cancer Institute, Bethesda, USA
3. Development of highly efficient and widely applicable CRISPR/Cas9-mediated cloning method of EBV genomes and its application to EBV-positive gastric cancer cell lines
 Teru Kanda, Aichi Cancer Center Research Institute, Nagoya, Japan
4. Association between cigarette smoking and oral EBV viral loads in China: a multicenter cross sectional study in 2013-2016
 Weihua Jia, Sun Yat-Sen University Cancer Center, Guangzhou, China
5. Determination and Genome-wide Analysis of EBV Sequences in EBV- associated Gastric Carcinoma from Guangdong, an endemic area of nasopharyngeal carcinoma 
Chun-kui Shao, Sun Yat-Sen University, Guangzhou, China
6. The dominating promoter variation of BRLF1 in nasopharyngeal carcinoma endemic area contributes to high efficacy of Epstein-Barr virus reactivation Jiangbo Zhang, Sun Yat-Sen University Cancer Center, Guangzhou, China

獵頭職場真相觀察

老闆要2個業務聯絡200個客戶...為什麼打完100通電話、「聽話」的人反而被解僱？
<撰文者江湖人稱S姐> 出處商業週刊按我

這是兩位業務在剛開始要做客戶開發時遇到的故事，可以拿來當借鏡。兩位員工暫且稱為小劉和小王好了，而這位主管的管理方式喜歡訓練員工思考。

主管：手邊這200個客戶跟聯繫窗口，你們分別聯繫100個，一周後我們來討論狀態。

小劉：好，我現在立馬來做。

小王 : 這100個名單裡面，哪些是比較重要但被忽略的客戶？哪些是久沒連繫的客戶？

討論一番以後，隔了一周，主管開會時分別和兩位業務詢問客戶狀態。

GRC NPC Index Page | EBV Meeting

• Clevers, Hans
• Delecluse, Henri-Jacques
• Fuchs, Elaine
• Futreal, Andrew
• Hildesheim, Allan
• Lieberman, Paul M.
• Liu, Fei-Fei
• Lo, Kwok-Wei
• Lo, Yuk-Ming Dennis
• Longnecker, Richard
• Lu, Xin
• Ma, Jun | Ngan, Roger | Bei, Jin-Xin
• Rooney, Cliona
• Tsai, Ming-Han
• Tsao, George SH
• Zeng, Mu-Sheng
• zur Hausen, Harald
• Unclassified (Hong Zheng, Honglin Chen, Brigette Ma, Wei Dai | TESSA, TGFBRI inhibitor, BPLF1 DUB)
• Group Photo

GRC NPC - Lieberman, Paul M.

2018 Madison Meeting
HENLE LECTURE
Paul M. Lieberman, Ph.D. The Wistar Institute Philadelphia, PA
Paul Lieberman obtained a Ph.D. at Johns Hopkins University, School of Medicine studying Epstein-Barr Virus reactivation in the laboratory of Dr. Gary and Diane Hayward. He completed a post-doctoral fellowship with Dr. Arnie Berk at UCLA investigating basic mechanisms of transcriptional activation by viral factors. He joined the Roche Institute of Molecular Biology as an Assistant Member and then moved to the Wistar Institute in Philadelphia in 1995. His research focuses on the molecular biology of Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) latency and persistence, with particular interests in epigenetic mechanisms and chromosome biology. His work combines biochemical, proteomic, and functional genomic methods to investigate regulation of viral latency, and how this contributes to viral carcinogenesis. The Lieberman group has leveraged this basic research to develop novel small molecule inhibitors and modulators of EBV and KSHV latency to treat viral-associated disease. Lieberman is presently the Hilary Koprowski Endowed Chair and Program Leader in Gene Expression and Regulation and the Director of the Center for Chemical Biology and Translational Medicine at the Wistar Institute.

Arch Pharm Res. 2017 Aug;40(8):894-905. doi: 10.1007/s12272-017-0939-5. Epub 2017 Aug 4.

DNA hypermethylation induced by Epstein-Barr virus in the development of Epstein-Barr virus-associated gastric carcinoma.

Choi SJ1, Shin YS2, Kang BW3, Kim JG3, Won KJ4, Lieberman PM5, Cho H6, Kang H7.

Author information

Abstract

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a recently recognized disease entity defined by the presence of EBV in gastric carcinoma cells. EBV infection causes major epigenetic alterations in the EBV genome and its cellular host genome, suggesting that EBV acts as a direct epigenetic driver for EBVaGC. One of the major epigenetic events in the viral and cellular genomes to control transcription is DNA hypo- or hyper-methylation. Particularly, local and global hypermethylation have been reported in EBVaGC. It is therefore important to understand the molecular mechanisms of DNA hypermethylation during EBVaGC carcinogenesis. To understand the functional roles of DNA methylation and suggest therapeutic target candidates for EBVaGC, we reviewed recent literature reporting DNA hypermethylation in EBVaGC. We summarized the identified candidate genes that are markedly hypermethylated in EBVaGC, which can potentially be targets for chemotherapies with demethylating agents. (pmid:28779374)

J Virol. 2017 Aug 9. pii: JVI.00804-17. doi: 10.1128/JVI.00804-17. [Epub ahead of print]

Coordinate Regulation of TET2 and EBNA2 Control DNA Methylation State of Latent Epstein-Barr Virus.

Lu F1, Wiedmer A1, Martin KA1, Wickramasinghe PJMS1, Kossenkov AV1, Lieberman PM2.

Author information

Abstract

Epstein-Barr Virus (EBV) latency and its associated carcinogenesis are regulated by dynamic changes in DNA methylation of both virus and host genomes. We show here that the Ten-Eleven Translocation 2 (TET2) gene, implicated in hydroxymethylation and active DNA demethylation, is a key regulator of EBV latency type DNA methylation patterning. EBV latency types are defined by DNA methylation patterns that restrict expression of viral latency genes. We show that TET2 mRNA and protein expression correlate with the highly demethylated EBV type III latency program permissive for expression of EBNA2, EBNA3s, and LMP transcripts. We show that shRNA depletion of TET2 results in a decrease in latency gene expression, but can also trigger a switch to lytic gene expression. TET2 depletion results in the loss of hydroxymethylated cytosine, and corresponding increase in cytosine methylation at key regulatory regions on the viral and host genomes. This also corresponded to a loss of RBP-jκ binding, and decreased histone H3K4 trimethylation at these sites. Furthermore, we show that the TET2 gene, itself, is regulated similar to the EBV genome. ChIP-Seq revealed that TET2 gene contains EBNA2-dependent RBP-jκ and EBF1 binding sites, and is subject to DNA methylation associated transcriptional silencing similar to EBV latency type III genomes. Finally, we provide evidence that TET2 colocalizes with EBNA2-EBF1-RBP-jκ binding sites, and can interact with EBNA2 by co-immunoprecipitation. Taken together, these findings indicate that TET2 gene transcripts are regulated similarly to EBV type III latency genes, and that TET2 protein is a cofactor of EBNA2 and co-regulator of the EBV type III latency program and DNA methylation state.

IMPORTANCE Epstein-Barr Virus(EBV) latency and carcinogenesis involves the selective epigenetic modification of viral and cellular genes. Here, we show that TET2, a cellular tumor suppressor involved in active DNA demethylation, plays a central role in regulating DNA methylation state during EBV latency. TET2 is coordinately regulated and functionally interacts with the viral oncogene EBNA2. TET2 and EBNA2 function cooperatively to demethylate genes important for EBV-driven B cells growth transformation. (PMID: 28794029)

PLoS Pathog. 2017 Aug 30;13(8):e1006596. doi: 10.1371/journal.ppat.1006596. eCollection 2017 Aug.

Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage.

De Leo A1, Chen HS1, Hu CC1, Lieberman PM1.

Author information

Erratum in

• Correction: Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage. [PLoS Pathog. 2018]

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus recognized as the principal causative agent of KS and primary effusion lymphoma (PEL). KSHV establishes persistent latent infection in B lymphocytes where viral gene expression is restricted, in part, by a cohesin-dependent chromosome conformation. Here, we show that endoplasmic reticulum (ER) stress induces a rapid, caspase-dependent cleavage of cohesin subunit RAD21. ER stress-induced cleavage of RAD21 correlated with a rapid and strong viral lytic transcriptional activation. This effect was observed in several KSHV positive PEL cells, but not in other B-cells or non-B-cell models of KSHV latency. The cleaved-RAD21 does not dissociate from viral genomes, nor disassemble from other components of the cohesin complex. However, RAD21 cleavage correlated with the disruption of the latency genome conformation as revealed by chromosome conformation capture (3C). Ectopic expression of C-terminal RAD21 cleaved form could partially induce KSHV lytic genes transcription in BCBLI cells, suggesting that ER-stress induced RAD21 cleavage was sufficient to induce KSHV reactivation from latency in PEL cells. Taken together our results reveal a novel aspect for control and maintenance of KSHV genome latency conformation mediated by stress-induced RAD21 cleavage. Our studies also suggest that RAD21 cleavage may be a general regulatory mechanism for rapid alteration of cellular chromosome conformation and cohesin-dependent transcription regulation. (PubMed: 28854249)

PLoS Pathog. 2018 Jan 19;14(1):e1006844. doi: 10.1371/journal.ppat.1006844. eCollection 2018 Jan.

RNA-Seq of Kaposi's sarcoma reveals alterations in glucose and lipid metabolism.

Tso FY1, Kossenkov AV2, Lidenge SJ1,3,4, Ngalamika O5, Ngowi JR3, Mwaiselage J3,4, Wickramasinghe J2, Kwon EH1, West JT1, Lieberman PM2, Wood C1.

Author information

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). It is endemic in a number of sub-Saharan African countries with infection rate of >50%. The high prevalence of HIV-1 coupled with late presentation of advanced cancer staging make KS the leading cancer in the region with poor prognosis and high mortality. Disease markers and cellular functions associated with KS tumorigenesis remain ill-defined. Several studies have attempted to investigate changes of the gene profile with in vitro infection of monoculture models, which are not likely to reflect the cellular complexity of the in vivo lesion environment. Our approach is to characterize and compare the gene expression profile in KS lesions versus non-cancer tissues from the same individual. Such comparisons could identify pathways critical for KS formation and maintenance. This is the first study that utilized high throughput RNA-seq to characterize the viral and cellular transcriptome in tumor and non-cancer biopsies of African epidemic KS patients. These patients were treated anti-retroviral therapy with undetectable HIV-1 plasma viral load. We found remarkable variability in the viral transcriptome among these patients, with viral latency and immune modulation genes most abundantly expressed. The presence of KSHV also significantly affected the cellular transcriptome profile. Specifically, genes involved in lipid and glucose metabolism disorder pathways were substantially affected. Moreover, infiltration of immune cells into the tumor did not prevent KS formation, suggesting some functional deficits of these cells. Lastly, we found only minimal overlaps between our in vivo cellular transcriptome dataset with those from in vitro studies, reflecting the limitation of in vitro models in representing tumor lesions. These findings could lead to the identification of diagnostic and therapeutic markers for KS, and will provide bases for further mechanistic studies on the functions of both viral and cellular genes that are involved. (PubMed: 29352292)

2016 GRC NPC

GRC NPC Group Photo_2016