《Cell》干细胞自我更新与分化平衡研究

　　

生物通报道，哈佛医学院，波士顿儿童医院Dana-Farber癌症研究所，霍华休斯医学研究所，麻省总医院以及威斯康辛大学医学与公共卫生学院的科学家在干细胞研究方面取得最新的进展，相关成果文章Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells公布在最新一期的Cell杂志上。

 

文章的通讯作者是哈佛医学院，霍华休斯医学院的Stuart H. Orkin教授，美国科学院院士，他主要从事干细胞方面的研究，尤其是造血系统的干细胞，以及癌症与干细胞间的关系。

 

组蛋白H3赖氨酸27（histone H3 lysine 27，H3K27me3）甲基化必须在PRC2抑制复合物的作用下才能完成，H3K27me3对胚胎干细胞的自我更新和分化具有重要的调控作用。

 

Polycomb group (PcG) 蛋白是一组通过染色质修饰调控靶基因的转录抑制子, 从生化和功能上它可以分成两个主要的核心蛋白复合体PRC1(Polycomb repressive complex 1)和PRC2(Polycomb repressive complex 2)。研究发现PcG蛋白不仅控制个体正确的发育模式, 而且与细胞的增殖、分化和肿瘤发生有关。

 

然而，关于PRC2的作用机制却不明确。在这篇文章中Stuart H. Orkin研究小组发现Jumonji家族成员，JMJ（JUMONJI或 JARID2）与PRC2的功能相关，与PRC2和H3K27me3共定位在染色质上，并具有调整PRC2的功能。

 

在体外实验中，Stuart H. Orkin研究小组发现，JMJ抑制PRC2甲基化酶的活性，同时增强胚胎干细胞H3K27me3在PRC2靶位上的标记。JMJ对PRC2的功能具有重要的调节作用。

 

这些研究成果表明，JMJ动态地调节PRC2的功能，以此来维持胚胎干细胞自我更新与分化间的平衡，一旦JMJ出现异常，可能导致胚胎干细胞自我更新于分化间的平衡被打破，影响胚胎干细胞的正常功能的维持。

（生物通 小茜）

生物通推荐原文检索

Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells

Xiaohua Shen1, Woojin Kim1, Yuko Fujiwara1, Matthew D. Simon5, Yingchun Liu4, Matthew R. Mysliwiec6, Guo-Cheng Yuan4, Youngsook Lee6 and Stuart H. Orkin1, 2, 3, , 

 

1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA

2 Howard Hughes Medical Institute, Boston, MA 02115, USA

3 Harvard Stem Cell Institute, Boston, MA 02115, USA

4 Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, MA 02115, USA

5 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA

6 Department of Anatomy, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA

 

Corresponding author

 

【Summary】

Trimethylation on histone H3 lysine 27 (H3K27me3) by Polycomb repressive complex 2 (PRC2) regulates the balance between self-renewal and differentiation of embryonic stem cells (ESCs). The mechanisms controlling the activity and recruitment of PRC2 are largely unknown. Here we demonstrate that the founding member of the Jumonji family, JMJ (JUMONJI or JARID2), is associated with PRC2, colocalizes with PRC2 and H3K27me3 on chromatin, and modulates PRC2 function. In vitro JMJ inhibits PRC2 methyltransferase activity, consistent with increased H3K27me3 marks at PRC2 targets in Jmj−/− ESCs. Paradoxically, JMJ is required for efficient binding of PRC2, indicating that the interplay of PRC2 and JMJ fine-tunes deposition of the H3K27me3 mark. During differentiation, activation of genes marked by H3K27me3 and lineage commitments are delayed in Jmj−/− ESCs. Our results demonstrate that dynamic regulation of Polycomb complex activity orchestrated by JMJ balances self-renewal and differentiation, highlighting the involvement of chromatin dynamics in cell-fate transitions.