呂昱瑋 Yu-Wei Leu

168, University Road, Min-Hsiung Chia-Yi Taiwan, R. O. C.
Tel: (05) 2720411 ext. 66507(Office) , 61518(Lab)
Fax: (05) 2722871
Email: bioywl@ccu.edu.tw

• 學歷

  Ph.D. 1993-2001 Intercollege Genetic program, The Pennsylvania State University, University Park, PA, USA.
  B.S. 1984-1988 Department of Biology, TungHai University, Taichung, Taiwan.

• 經歷

  2004-Present Assistant Professor,
  　Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Chia-Yi, Taiwan.
  2003-2004 Postdoctoral Research Associate,
  　Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA (The whole lab moved from MO to OH).
  2002-2003 Postdoctoral Research Associate,
  　Department of Pathology and Anatomical Science, Ellis Fischel Cancer Center, Columbia, MO, USA.
  2001-2002 Postdoctoral Research Associate,
  　Ernest Gallo Clinic & Research Center, University of California, San Francisco, Emeryville, CA, USA.

• 研究興趣與專長

  Cancer & Functional Epigenomics

  Current Working Model:
  

• 1. 成體幹細胞之分化及癌化間對位性基因體關聯性之探討(Epigenomic Association between Somatic Stem Cell Differentiation and Tumerogenesis )：

  

  去氧核醣核酸的甲基化和組織蛋白上的修飾等對位性基因體的改變在細胞的分化及癌化過程中歷歷可見。諸多實驗已證明：適當地維持對位性基因體的平衡為細胞正常分化所須，並可確保細胞不致於癌化。對位性基因體的修飾不但具有可逆性，亦能於細胞分裂、分化過程中受到保存甚或累積，因此對位性基因體的修飾被廌為藥物設計發展的目標及作為追蹤細胞分化及癌化過程的生物標記。本計劃亦據此發展綜和的對位性基因體研究方法。

  對位性基因體修飾作為生物標記的必要條件為：(1)其發生和基因表達相關；(2)其發生並非完全隨機。此二要件在我們以前的結果中已得到初步驗證。本計畫即在此基礎之上更加證明以對位性基因體修飾作為生物標記的正當性，而實際作法則為追蹤在細胞的分化及癌化過程中對位性基因體修飾的改變並據此找出其關聯性。

  我們已測得在骨髓間質體幹細胞分化成為肝細胞過程中對位性基因體修飾的連續性改變，此連續性的改變不但具有一特定的起始點 (即幹細胞) 並和一般多源性的疾病如癌症有所區別。若能比較肝細胞在正常分化及癌化過程中對位性基因體修飾的差異改變，或能找出肝癌細胞的真正起源。而本計劃即提出一套新的、有系統的研究平臺以達此目的。
  

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• 2. 對位基因性修飾作為乳癌進程痕跡暨其檢定之生物標記的建立及評量 (Establish and Validate Epigenetic Modifications as Breast Cancer Progression Relic and Diagnostic Biomarkers)：

  

  在乳癌的形成及擴增的情形之中，雌性激素的訊息傳導扮演著決定性的角色。除了遺傳因素之外，雌性激素受體下游基因的表現也會受到對位基因(epigenetic)所調控並隨著乳癌的發展而改變。因此，我們設計一套生物系統學(System Biology)的方法來監測雌性激素受體及其下游基因在乳癌發展過程中的改變，並希望能借此建立以雌性激素受體下游基因之對位基因性改變作為追蹤乳癌擴展及癒後之生物標計。此一系列的研究將始於利用短干擾性核醣核酸 (siRNA)來降低雌性素受體在乳癌細胞株中的表達及功能。接著利用免疫沈澱法(immunoprecipitation)配合生物晶片(microarray)來發掘整個基因體中受雌性素受體調控的下游基因。一旦雌性素受體的表達被抑制，其下游基因的啟動子(promoter)區域會進行一連串的組織蛋白(histone)修飾、抑制性蛋白(如HDAC1、DNMTs和MeCP2)的連接及去氧核醣核酸(DNA)的甲基化(methylation)等對位遺傳方式的改變。當短干擾性核醣核酸作用時間越長，下游基因所受到的抑制越不可逆。因這些對位遺傳上的修飾可跟著細胞的分裂增生而傳到子代細胞，故這種增生的功能亦代表其具有作為追蹤癌症擴展之生物標記的能力。本計劃規劃的實驗即在於: 首先檢視在細胞株所做的發現能否在人類腫瘤組織中發現。亦即在雌性素受體表達較少的腫瘤組織，其下游基因的啟動子區域應具有較多的去氧核醣核酸甲基化的現象。我們將發展具有特異性的甲基化偵測螢光檢定法(Methyl-light)以大量篩檢病人下游基因啟動子位置的甲基化改變。這些改變會進一步利用甲基化特殊檢定生物晶片的方法及甲基化專一性化學修飾後基因序列的求得而得到驗証。這些實驗數據將和病理上的資料進行比對分析。生物資訊及統計學的方法將被應用於尋找在這些下游基因之中其對位遺傳特性最適於追?癌症擴展者。於發現之後將再利用短干擾性核醣核酸以研究其功能及和腫瘤的關連。如此循環利用此系統生物學的策略，並將其運用於其他和腫瘤生成相?的訊息傳導通道研究上，將可找到適合追蹤各種癌症的生物標記。

• 3. Invented Epigenomics modofication methodology：

  Patenting

• Major Tools

  (1) 4 CpG microarray and their validations：

  ChIP-on-chip
  

  ECIST
  

  DMH
  

  Chromatin Landscaping
  

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• (2) siRNA

  

  (3) DNA Methylation

  
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• (4) Biostatistics

  

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• 論文與著作

  • Yu-Wei Leu and Tim H.-M. Huang. Global DNA Methylation in the Modeling of Tumoral Progression. Cell Science Reviews, 4, No. 2: 2007(ISSN1742-8130).
  • Pearlly S. Yan, Venkataramu Chinnambally, Ashraf Ibrahim, Joseph C. Liu, Nils Diaz, Barbar Centeno, Frank Weber, Yu-Wei Leu, Charis Eng, Timothy J. Yeatman, Tim H.-M. Huang. Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue. Clin Cancer Research, 63: 6626-6636, 2006.
  • Alfred S. Cheng, Victor X. Jin, Meiyun Fan, Laura T. Smith, Sandya Liyanarachchi, Pearlly S. Yan, Yu-Wei Leu, Michael W. Chan, Christoph Plass, Kenneth P. Nephew, Ramana V. Davuluri, Tim H.-M. Huang. Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to ER-responsive promoter. Mol. Cell, 21: 393-404, 2006.
  • Hsin-Pai Li, Yu-Wei Leu and Yu-Sun Chang. Epigenetic changes in virus-associated human cancers. Cell Research, 15: 262-271, 2005.
  • Yu-Wei Leu, Pearlly S. Yan, Meiyun Fan, Victor X. Jin, Joseph C. Liu, Susan H. Wei, Ramana V. Davuluri, Christoph Plass, Kenneth P. Nephew, and Tim H.-M. Huang. Loss of estrogen signaling leads to epigenetic silencing of its target genes in breast cancer. Cancer Research, 64:8184-8192, 2004.
  • Victor X Jin*, Yu-Wei Leu*, Sandya Liyanarachchi, Hao Sun, Kenneth P. Nephew, Tim H.-M Huang, Ramana V Davuluri. Identifying estrogen receptor a target genes using integrated computational genomics and chromatin immunoprecipitation microarray. Nucleic Acids Res, 32: 6627-6635, 2004. (*contributed equally to this paper).
  • Yu-Wei Leu, Farahnaz Rahmatpanah, Huidong Shi, Joseph C. Liu, Susan H. Wei, Pearlly S. Yan, Tim Hui-Ming Huang. Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Research, 63: 6110-6115, 2003.
  • Huidong Shi, Susan Wei, Yu-Wei Leu, Farahnaz Rahmatpanah, Joseph Liu, Pearlly Yan, Kenneth P. Nephew, Tim H.-M. Huang. Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation, and histon acetylation. Cancer Research, 63: 2164-2171, 2003.
  • Pearlly S. Yan, Huidong Shi, Farahnaz Rahmatpanah, Tim Hsiao, Andrew Hsiao, Yu-Wei Leu, Joseph C. Liu, Tim H.-M. Huang. Differential distribution of DNA methylation within the RASSF1A CpG island in breast cancer. Cancer Research, 63: 6178-6186, 2003.
  • Yu-Wei Leu and Tim Hui-Ming Huang. Diagnostic arrays for epigenetic markers. Toxicologic Pathology, 31 (1) 140-170, 2003.

• Book Chapters

  Yu-Wei Leu, Alfred S.-L and Tim Hui-Ming Huang. (2006) Use of CpG island microarray to interrogate the cancer epigenome. Promoter and CpG island Microarrays (Winegarden NA, Takashi M, eds). DNA Press (ISBN: 0-9748765-6-9).

• Abstracts

  • Yu-Wei Leu, Shu-Huei Hsiao, Kuan-Der Lee, Min-Jen Tseng, Wei-Sheng Sun, Hao-Chun Chang, Chia-Chen Hsu, Yu-Chin Lin, Chou-Yu Chen, Yi-Chen Hung, Ching-Chu Yen, Kun-Tu Yeh, Shaw-Jeng Tsai, Hsiao-Fang Sunny Sun, Yu-Sun Chang, and Tim H.-M. Huang (2007) Elements in Functional Epigenomic Modeling for Somatic Stem Cell Differentiation and Tumorigenesis. 2007 Symposium of Bioinformatics and Systems Biology in Taiwan.
  • Yu-Wei Leu, Shu-Huei Hsiao, Kuan-Der Lee, Min-Jen Tseng, Wei-Sheng Sun, Chia-Chen Hsu, Hao-Chun Chang, Yi-Chen Hung, Kun-Tu Yeh, Shaw-Jeng Tsai, Hsiao-Fang Sunny Sun, Yu-Sun Chang, and Tim H.-M. Huang. (2007) Bivalent DNA methylation in cell fate determination. 第二十三屆生物夏令營, 溪頭.
  • Yu-Wei Leu, Shu-Huei Hsiao, Kuan-Der Lee and Min-Jen Tseng (2007) Epigenomic Association between Somatic Stem Cell Differentiation and Tumerogenesis. National Research Program for Genomic Medicine (NPRGM) annual progress meeting, Taipei, Taiwan.
  • Yu-Wei Leu, Shu-Huei Hsiao, Kuan-Der Lee and Min-Jen Tseng (2006) Epigenomic Association between Somatic Stem Cell Differentiation and Tumerogenesis. National Research Program for Genomic Medicine (NPRGM) progress meeting, Taipei, Taiwan.
  • Yu-Wei Leu, Shu-Huei Hsiao, Kuan-Der Lee and Min-Jen Tseng (2006) Epigenomic Association between Somatic Stem Cell Differentiation and Tumerogenesis. National Research Program for Genomic Medicine (NPRGM) progress meeting, Taipei, Taiwan.
  • Pearlly S. Yan, Venkataramu Chinnambally, Ashraf Ibrahim, Joseph C. Liu, Nils Diaz, Barbara Centeno, Frank Weber, Yu-Wei. Leu, Charis Eng, Timothy J. Yeatman, Tim H.-M. Huang. (2006) Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Amer. Assoc. Cancer Res. 97th Annual meeting, Washington DC.
  • Alfred S Cheng, Yu-Wei Leu, Mei Y Fan, Pearlly S Yan, Kenneth P Nephew, Tim H Huang. (2004) Use of chromatin landscaping microarray to detect histone modifications in estrogen-responsive promoters. Chromatin, Chromosomes and Cancer Epigenetics, American Association for Cancer Research. Waikoloa, Hawaii.
  • Yu-Wei Leu, Pearlly S. Yan, Meiyun Fan, Victor X. Jin, Joseph C. Liu, Susan H. Wei, Ramana V. Davuluri, Christoph Plass, Kenneth P. Nephew, and Tim H.-M. Huang. (2004) Triggering of specific DNA methylation by disrupting the estrogen signaling pathway. Third Annual Post Graduate and Graduate Research Day, the Ohio State University. Columbus, OH.
  • Victor X Jin, Sandya Liyanarachchi, Hao Sun, Ramana V Davuluri , Yu-Wei Leu, Tim H.-M Huang. (2004) A computational Strategy for genome-wide ananlysis of the ER target genes. Third Annual Post Graduate and Graduate Research Day, the Ohio State University. Columbus, OH.
  • Yu-Wei Leu, Pearlly S. Yan, Meiyun Fan, Victor X. Jin, Joseph C. Liu, Susan H. Wei, Ramana V. Davuluri, Christoph Plass, Kenneth P. Nephew, and Tim H.-M. Huang. (2003) Triggering of specific DNA methylation by disrupting the estrogen signaling pathway. Jensen Symposium. Cincinnati, Ohio.
  • Victor X. Jin, Yu-Wei Leu, Meiyun Fan, Kenneth P. Nephew, Tim H.-M. Huang, and Ramana V. Davuluri. (2003) A computational Strategy for genome-wide ananlysis of the ER target genes. Jensen Symposium. Cincinnati, Ohio.
  • Yu-Wei Leu, Farahnaz Rahmatpanah, Huidong Shi, Joseph C. Liu, Susan H. Wei, Pearlly S. Yan, Tim Hui-Ming Huang. (2003) Effects of RNA interference on DNA methyltransferase gene expression and DNA methylation. Amer. Assoc. Cancer Res. 94th Annual meeting, Washington DC.
  • Pearlly S. Yan, Farahnaz Rahmatpanah, Joseph C. Liu, Tim Hsiao, Andrew Hsiao, Yu-Wei Leu, Huidong Shi, Tim H.-M. Huang. (2003) Disparity of methylation distribution within the RASSF1A CpG island in breast cancer. Amer. Assoc. Cancer Res. 94th Annual meeting, Washington DC.
  • Yu-Wei Leu and Tim Hui-Ming Huang. (2003) Diagnostic arrays for epigenetic markers. Aspen Cancer Conference, Aspen, Colorado.