Pygo2是Beta-catenin的结合蛋白，然而其在哺乳动物中的生物学功能和调节Wnt信号的分子机理仍不清楚。厦门大学李博安教授课题组利用基因敲除小鼠模型进行研究，发现Pygo2基因敲除小鼠乳腺发育严重受损，Pygo2 调节了乳腺胚胎期和成体干细胞/祖细胞的扩张性自我更新。Pygo2 通过募集H3K4甲基化转移酶调节染色质的甲基化，使染色质处于激活状态；另一方面，其PHD结构域又能够与H3K4Me3染色质标记直接结合，增强转录因子复合体的稳定性，同时行使表观调控和启动特异性基因转录的作用。
这一发现表明，阻断Pygo2的功能可以作为一个潜在的治疗靶点，抑制乳腺细胞的过度增生和Wnt信号的过度激活，为乳腺癌的治疗奠定基础，相关的研究正在进行中。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Cell Biology, Vol. 185, No. 5, 811-826 doi:10.1083/jcb.200810133
Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation
Bingnan Gu1, Peng Sun1, Yuanyang Yuan1,4,5, Ricardo C. Moraes6,7, Aihua Li1, Andy Teng1, Anshu Agrawal3, Catherine Rhéaume1, Virginia Bilanchone1, Jacqueline M. Veltmaat8, Ken-Ichi Takemaru9, Sarah Millar10,11, Eva Y.-H.P. Lee1, Michael T. Lewis6,7, Boan Li1,4,5, and Xing Dai1,2
1 Department of Biological Chemistry, 2 Developmental Biology Center, and 3 Department of Medicine, University of California, Irvine, Irvine, CA 92697
4 Department of Biomedical Sciences and 5 Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
6 Lester and Sue Smith Breast Center and 7 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
8 Institute of Molecular and Cell Biology, A*STAR, Proteos, 138673 Singapore
9 Department of Pharmacological Sciences, State University of New York, Stony Brook, Stony Brook, NY 11794
10 Department of Dermatology and Department of 11 Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Recent studies have unequivocally identified multipotent stem/progenitor cells in mammary glands, offering a tractable model system to unravel genetic and epigenetic regulation of epithelial stem/progenitor cell development and homeostasis. In this study, we show that Pygo2, a member of an evolutionarily conserved family of plant homeo domain–containing proteins, is expressed in embryonic and postnatal mammary progenitor cells. Pygo2 deficiency, which is achieved by complete or epithelia-specific gene ablation in mice, results in defective mammary morphogenesis and regeneration accompanied by severely compromised expansive self-renewal of epithelial progenitor cells. Pygo2 converges with Wnt/β-catenin signaling on progenitor cell regulation and cell cycle gene expression, and loss of epithelial Pygo2 completely rescues β-catenin–induced mammary outgrowth. We further describe a novel molecular function of Pygo2 that is required for mammary progenitor cell expansion, which is to facilitate K4 trimethylation of histone H3, both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes.
