Pygo2是Beta-catenin的結(jié)合蛋白,，然而其在哺乳動物中的生物學(xué)功能和調(diào)節(jié)Wnt信號的分子機(jī)理仍不清楚,。廈門大學(xué)李博安教授課題組利用基因敲除小鼠模型進(jìn)行研究,，發(fā)現(xiàn)Pygo2基因敲除小鼠乳腺發(fā)育嚴(yán)重受損,，Pygo2 調(diào)節(jié)了乳腺胚胎期和成體干細(xì)胞/祖細(xì)胞的擴(kuò)張性自我更新,。Pygo2 通過募集H3K4甲基化轉(zhuǎn)移酶調(diào)節(jié)染色質(zhì)的甲基化,，使染色質(zhì)處于激活狀態(tài),；另一方面，其PHD結(jié)構(gòu)域又能夠與H3K4Me3染色質(zhì)標(biāo)記直接結(jié)合,，增強(qiáng)轉(zhuǎn)錄因子復(fù)合體的穩(wěn)定性,，同時行使表觀調(diào)控和啟動特異性基因轉(zhuǎn)錄的作用。
這一發(fā)現(xiàn)表明,，阻斷Pygo2的功能可以作為一個潛在的治療靶點,，抑制乳腺細(xì)胞的過度增生和Wnt信號的過度激活，為乳腺癌的治療奠定基礎(chǔ),，相關(guān)的研究正在進(jìn)行中,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
