Dr. Wang, Shu-Ping 王書品 博士

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Dr. Wang, Shu-Ping
王書品 博士

Assistant Research Fellow
助研究員

    • B.S. National Sun Yat-Sen University
    • M.S. National Tsing-Hua University
    • Ph.D. National Defense Medical Center
    • Postdoc. The Rockefeller University, New York
  • 02-2789-9122 (Lab) (Room No: 540)
  • 02-2652-3073 (Office)
  • spwang@ibms.sinica.edu.tw
Specialty:
  • Molecular oncology, Cancer epigenetics
  • Biochemically defined cell free system
  • CRISPR-based genetic/epigenetic editing

RESEARCH

REASEARCH INTERESTS & GOALS

My lab’s long-term research interest is to elucidate epigenetic regulatory mechanisms related to the fundamental biological issues, including developmental defect and cancer. The research focus is to decipher how the key epigenetic regulators, including histone lysine methyltransferases (HMTs) and demethylases, control target gene transcription through enhancer landscape modifications under physiological and disease conditions. With all the proposed research programs, our final goal is to utilize the CRISPR-based epigenome editing technology and/or small molecule inducers/inhibitors to precisely manipulate gene expression programs that can determine cell type specification or correct misregulated gene expressions in cancer diseases.

 

RESEARCH DIRECTIONS & PROJECTS

Targeting H3K4 HMTs Mixed Lineage Leukemia 3/4 (MLL3/4) in human cancers

Although the cancer genome sequencing data support a key tumor suppressor role of MLL3 or MLL4 in a number of human cancers, there are certain cases in which these histone-modifying enzymes may function as oncogenic cofactors in driving tumorigenesis. In this research theme, we would like to elucidate the potential MLL3/4 oncogenic functions in certain cancer types and identify small-molecular inhibitors of MLL3/4 as a potential targeted therapy for these cancers.

 

A H3K4 methyltransferase/demethylase axis regulates cancer progression

While H3K4 tri-methylation (H3K4me3) positively regulates gene transcription at promoters, recent studies indicated a potential role of H3K4me3 in enhancer activation. The KDM5C demethylase complex functions to maintain the enhancer activity at normal levels for majority of individual and super enhancers, whereas deficiency in this H3K4 demethylase complex can increase the levels of enhancer-associated H3K4me3 and upregulate enhancer activities, leading to oncogene activation and cancer progression. In this project, we would like to identify the key H3K4 HMT(s) responsible for enhancer-associated H3K4me3 and elucidate the underlying mechanism of the novel H3K4 methyltransferase/ demethylase axis functions in cancer progression.

 

Mapping enhancer regulatory elements of oncogenes and tumor-suppressor genes

Enhancers contain various DNA sequecnes that are essential for precise gene regulation and can communicate with target promoters by forming looping structures. Importantly, enhancer malfunction can casue abnormal expression of target oncogenes or tumor suppressor genes, inducing tumorigenesis. Thus, a complete understaning of oncogene/tumor suppressor gene-associated enhancer sequences and genomic locations will benefit to the cancer epigenome profiling. In this research direction, we would like to set up a pipline for the identification and chracterization of key enhancers with their target genes in cancer epigenomes by ChIP-sequencing, CRISPR inteference (CRISPRi), and 4C (chromatin conformation caprture)-sequencing technologies.

研究介紹

研究興趣與目標

本實驗室的長期研究興趣是闡明與基本生物學問題(包括發育缺陷和癌症)相關的表觀遺傳調控機制。研究重點是破譯關鍵的表觀遺傳調節因子,包括組蛋白甲基轉移酶 (HMTs) 和去甲基化酶,如何在生理和疾病條件下通過增強子景觀修飾來控制目標基因的轉錄。對於所有提議的研究計劃,我們的最終目標是利用基於 CRISPR 的表觀基因組編輯技術和小分子誘導劑/抑製劑來精確操縱基因表達程序,從而確定細胞類型規範或糾正癌症疾病中錯誤調節的基因表達。

 

研究方向和項目

確立 MLL3/4甲基轉移酶為抗腫瘤標靶治療之靶標

儘管癌症基因組測序數據支持 MLL3 或 MLL4 在許多人類癌症中可能扮演關鍵之腫瘤抑制角色,但在某些情況下,這些組蛋白修飾酶也可能作為致癌輔助因子,並參與驅動腫瘤發生之過程。在這個研究主題中,我們想闡明某些癌症類型中潛在的 MLL3/4 致癌功能,確定 MLL3/4 為抗腫瘤標靶治療之靶標,並設計小分子抑製劑作為這些癌症的潛在靶向治療。

 

探討H3K4 甲基轉移酶/去甲基化酶基軸調節癌症進展

雖然 H3K4 三甲基化 (H3K4me3) 在主要修飾啟動子以正向調節基因轉錄,但最近的研究表明H3K4三甲基化同時也具有激活增強子的潛在功能。KDM5C H3K4去甲基酶複合物可以將大多數基因組上的增強子的活性維持在正常水平; 然而當這種 H3K4 去甲基酶複合物失能,則會大幅地增加增強子上的 H3K4三甲基化,強化增強子活性,進而引發致癌基因的過度表現並促使癌症進展。在這個研究項目中,我們想確定負責增強子H3K4三甲基化的關鍵H3K4甲基轉移酶,並闡明此新穎的H3K4甲基轉移酶/去甲基酶基軸作用於癌症進展中的潛在分子機制。

 

繪製致癌基因和抑癌基因的增強子調控元件

增強子包含各式各樣的DNA序列,這些序列對於精確的基因調控至關重要,並且可以通過與目標啟動子形成環形結構而與之進行溝通。重要的是,增強子功能發生障礙會導致目標致癌基因或抑癌基因的異常表現,從而誘發腫瘤發生。因此,全面了解致癌基因與腫瘤抑制基因相關的增強子序列和其在基因組的位置將有利於癌症表觀基因組分析。在這個研究方向,我們希望建立一套分析與鑑定系統,通過 ChIP 測序、CRISPR 干擾 (CRISPRi) 和 4C(染色質空間構象捕捉)測序技術,鑑定並分析癌症表觀基因組中關鍵增強子及其目標致癌或抑癌基因之相關性。

HIGHLIGHT 重要成果

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