Cao Ru, Zhang Yi
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mol Cell. 2004 Jul 2;15(1):57-67. doi: 10.1016/j.molcel.2004.06.020.
Recent studies have revealed the intrinsic histone methyltransferase (HMTase) activity of the EED-EZH2 complex and its role in Hox gene silencing, X inactivation, and cancer metastasis. In this study, we focus on the function of individual components. We found that the HMTase activity requires a minimum of three components-EZH2, EED, and SUZ12-while AEBP2 is required for optimal enzymatic activity. Using a stable SUZ12 knockdown cell line, we show SUZ12 knockdown results in cell growth defects, which correlate with genome-wide alteration on H3-K27 methylation as well as upregulation of a number of Hox genes. Chromatin immunoprecipitation (ChIP) assay identified a 500 bp region located 4 kb upstream of the HoxA9 transcription initiation site as a SUZ12 binding site, which responds to SUZ12 knockdown and might play an important role in regulating HoxA9 expression. Thus, our study establishes a critical role of SUZ12 in H3-lysine 27 methylation and Hox gene silencing.
近期研究揭示了EED-EZH2复合物的内在组蛋白甲基转移酶（HMTase）活性及其在Hox基因沉默、X染色体失活和癌症转移中的作用。在本研究中，我们聚焦于各个组分的功能。我们发现HMTase活性至少需要三个组分——EZH2、EED和SUZ12，而AEBP2对于最佳酶活性是必需的。使用稳定的SUZ12敲低细胞系，我们发现SUZ12敲低导致细胞生长缺陷，这与全基因组范围内H3-K27甲基化的改变以及多个Hox基因的上调相关。染色质免疫沉淀（ChIP）分析确定了位于HoxA9转录起始位点上游4 kb处的一个500 bp区域为SUZ12结合位点，该位点对SUZ12敲低有反应，可能在调节HoxA9表达中起重要作用。因此，我们的研究确立了SUZ12在H3-赖氨酸27甲基化和Hox基因沉默中的关键作用。
