Dr. Wang, Shu-Ping 王書品 博士

Brand

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

  • 02-27899122 (Lab) (Room No: 540)
  • 02-26523073 (Office)
  • spwang@ibms.sinica.edu.tw
Specialty:
  • Molecular oncology, Cancer epigenetics
  • Biochemically defined cell free system
  • CRISPR-based genetic/epigenetic editing

RESEARCH

Epigenetics is the study of heritable alternations in gene expression that involve changes in DNA and histone modifications as well as chromatin structures. Epigenetic regulation of gene expression is central for embryogenesis, cell-fate decisions and other important cellular processes. Thus, aberrant epigenetic changes are thought to be the most common cause of gene alterations in the development of various diseases, such as cancer. These mutations often misregulate enhancers that normally control cell-type specific gene expression programs. Such altered gene expression can be caused by direct mutations on enhancer elements or as a result of irregular epigenetic regulators that control enhancer activity. Among enhancer regulators, the Mixed Lineage Leukemia 4 (MLL4/KMT2D) complex (MLL4C) and Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2) are the most important chromatin modifiers that modulate histone methylations as well as chromatin structures associated with gene activation (H3K4 methylation/loose structure) and repression (H3K27 methylation/compact structure), respectively. Somatic mutations of the complex subunits (especially the catalytic subunits, e.g., MLL4, UTX and EZH2) are frequently found in human cancers. However, much less is known about the interplay of MLL4C and PRC1/2 in the control of chromatin structure and gene expression, and how cancer-associated mutations lead to disorder of chromatin landscapes and dysregulation of target gene transcription.
By focusing on MLL4C, PRC1/2 and the cognate histone modifications, our laboratory aims to explore how chromatin-modifying complexes coordinately control specific chromatin landscapes for target gene transcription in both normal and pathological conditions. Through a combination of genetic models, genome-wide profiling, cell-free (in vitro) chromatin-templated factor binding and transcription assays, cryo-EM structural analyses and CRISPR/Cas9-mediated domain screens, we aim to (1) profile cancer epigenome with somatic mutations in the catalytic subunits of MLL4C and/or PRC1/2; (2) determine the molecular architectures of MLL4C and PRC1/2 as well as their interplay with nucleosomes by cryo-EM; (3) identify and characterize functional protein domains that are critical for the development or suppression of cancer. 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.

研究介紹

表觀遺傳學係指不改變DNA序列,而透過DNA、組蛋白修飾以及染色質結構的變化來影響基因表現的研究。此調控在胚胎發育、細胞命運決定以及其他生理功能扮演重要的角色。因此,變異的表觀遺傳變化所造成的基因表現異常被視為是促成各種疾病 (例如癌症) 的主要成因。這類的突變通常導致增強子功能失調 (增強子係為基因體上可控制特定細胞類型之基因表現的DNA序列)。造成增強子失能的原因可能是表觀遺傳調節蛋白發生變異,或是增強子序列直接發生突變。
在眾多的增強子調節蛋白中, MLL4  (也稱作KMT2D) 和PRC1/2 是重要的染色質修飾酶,可以調節組蛋白甲基化,影響染色質結構的密度,進而調控基因表現。這些染色質修飾酶通常以複合體的形式存在,且在人類癌症中經常發現它們的組成分子發生體細胞突變,特別是修飾酶分子 (例如MLL4、 UTX和EZH2)。然而目前仍然不清楚MLL4和PRC1/2複合體在染色質結構和基因表現控制中是如何相互作用,以及癌症相關突變是如何導致染色質修飾異常和下游基因轉錄失調。
因此,透過研究MLL4和PRC1/2複合體,以及相對應的染色質修飾,本實驗室旨在探索這些重要的染色質修飾複合體如何在正常和病理條件下協調控制下游基因轉錄。我們將使用各式的研究方法和工具,包括分子生物技術,全基因組分析,無細胞(體外)染色質模板因子結合和轉錄試驗,冷凍電鏡結構分析和CRISPR/Cas9功能蛋白區域篩選,並綜合各種研究成果來(1)描繪具有MLL4或PRC1/2複合體體細胞突變的癌症表觀基因組; (2)分析MLL4和PRC1/2複合體的分子結構以及它們如何與核小體相互作用; (3)找出對於抑制或是促進癌症發展中重要的功能蛋白區域。依據這些研究基礎,我們最終的目標是應用CRISPR表觀基因組編輯技術,以及開發小分子誘導劑/抑製劑來精準操縱基因表現程序,以此導正發育細胞走向正確的命運,或糾正癌細胞中錯誤調節的基因表現。

PUBLICATIONS 研究論文

Record 11 to 13, total of 13 records
Top