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沈晓骅

 

沈晓骅 

 

电子邮件:xshen(at)tsinghua(dot)edu(dot)cn

电话:+86-10-62781029

实验室主页:http://xstem.med.tsinghua.edu.cn/?lang=zh 

 

科研概述:

高等生物由上百种类型的细胞组成, 这些细胞拥有相同的遗传物质,但是不同的表观遗传状态、基因表达和细胞功能。因此, 发育的本质就是建立多种表观遗传状态的过程。然而,高等生物上百种、细胞特有的表观遗传状态是如何被建立的呢?一旦建立,它们又是被维持及解读的?我们主要以小鼠多能性干细胞为模型,并结合癌症细胞和小鼠模型,研究发育和干细胞分化过程中,信号通路及细胞特有的调控因子(包括蛋白和非编码RNA分子)如何与表观遗传调控机制(以Polycomb蛋白介导的H3K27me3为例)相互作用,指示或引导表观遗传酶在不同细胞、不同的染色质区域,建立不同的表观遗传修饰,从而选择性地表达部分基因,决定细胞命运和功能。以上表观遗传机制的突变又如何导致人类疾病,特别是癌症。研究成果将会提供重要的框架在系统和分子水平上认识表观遗传机制在基因调控、干细胞分化、发育和疾病中的作用,促进人工操控细胞命运和干细胞疗法的临床实现,并提供新颖的药物线索治疗癌症。

多能干细胞自我更新和定向分化及肿瘤发生过程中的分子机理,具体研究内容包括:
1、表观遗传调控机制;
2、长链非编码RNA;
3、染色质结构和基因表达调控。

 

 

主要论文著作:

1.     Yin Y, Yan P, Lu J, Song G, Zhu Y, Li Z, Zhao Y, Shen B, Huang X, Zhu H, Orkin SH, Shen X. (2015). Opposing roles for the lncRNA Haunt and its genomic locus in regulating HOXA gene activation during embryonic stem cell differentiation. Cell Stem Cell. 16:1-13.

• Recommended in F1000Prime as being of special significant in its field by F1000 Faculty Member.

2.      Ding J, Huang X, Shao N, Zhou H, Lee D, Faiola F, Fidalgo M, Guallar D, Saunders A, Shliaha P, Wang H, Waghray A, Papatsenko D, Sánchez-Priego C, Li D, Yuan Y, Lesmischka I, Shen L, Kelley K, Deng H, Shen X, Wang J. (2015). Sox2-Dependent Functions of Tex10 in Epigenetic Control of the Super-Enhancer Activity for Pluripotency and Reprogramming. Cell Stem Cell. 16(6):653-68.

3.      Yuan G, Ma B, Yuan W, Zhang Z, Chen P, Ding X, Feng L, Shen X, Chen S, Li G, Zhu B. (2013). Histone H2A ubiquitination inhibits the enzymatic activity of H3 lysine 36 methyltransferases. J Biol Chem. 288(43):30382-42.

4.      Sakaki K, Yoshina S, Shen X, Han J, DeSantis MR, Xiong M, Mitani S, Kaufman RJ. (2012). RNA surveillance is required for endoplasmic reticulum homeostasis. Proc Natl Acad Sci USA. 109(21):8079-84.

5.      He A, Shen X, Ma Q, Cao J, Gise AV, Zhou P, Wang G, Marquez VE, Orkin SH, Pu WT. (2012). PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes & Development.  26: 37-42.

6.      Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya EV, Meyerson M, Kaelin WG Jr, Yan Q. (2011). Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci USA. 108(33):13379-86.

7.      Wilson BG, Wang X, Shen X, McKenna ES, Lemieux ME, Cho Y, Koellhoffer EC, Pomeroy SL, Orkin SH, Roberts CWM. (2010). Epigenetic antagonism between Polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 18(4):316-28.

8.      Shen X, Kim W, Fujiwara Y, Simon MD, Liu Y, Mysliwiec MR, Yuan G, Lee Y, Orkin SH. (2009). Jumonji modulates Polycomb activity and self-renewal versus differentiation of stem cells. Cell. 139(7): 1303-1314.

9.      Shen X, Liu Y, Hsu Y, Fujiwara Y, Kim J, Mao X, Yuan G, and Orkin SH. (2008). EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell. 32(4):491-502.

10.    Kim J, Chu J, Shen X, Wang J, Orkin SH. (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 132(6): 1049-61.

11.   Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH. (2006). A protein interaction network for pluripotency of embryonic stem cells. Nature. 444(7117):364-8.

12.   Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ. (2006). Endoplasmic reticulum stress activates cleavage of CREBh to induce a systemic inflammatory response. Cell. 124(3): 587-99.

13.   Shen X, Ellis RE, Sakaki K and Kaufman RJ. (2005). Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genetics. 1(3):e37.

14.   Shen X, Ellis RE, Lee K, Liu C, Yang K, Solomon A, Yoshida H, Morimoto R, Kurnit DM, Mori K, and Kaufman RJ. (2001). Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell. 107: 893-903.

  

 

 

 

 

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