本文選題：UHRF2 + 液相串聯(lián)質(zhì)譜�。� 參考：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2016年博士論文

【摘要】：UHRF家族蛋白是以具有多個(gè)結(jié)構(gòu)域?yàn)樘攸c(diǎn)的一組蛋白,包含4個(gè)成員。其中,以UHRF1研究最多,UHRF1被報(bào)道在多個(gè)生物學(xué)過程中發(fā)揮重要作用,比如它能夠維持DNMT1介導(dǎo)的DNA甲基化。UHRF2具有與UHRF1相似的序列和結(jié)構(gòu)域。這種結(jié)構(gòu)上的相似性預(yù)示著兩個(gè)蛋白之間功能的保守性。如同UHRF1,UHRF2也能夠識別半甲基化DNA以及甲基化的組蛋白,在體外也被證明與DNMTs以及組蛋白甲基轉(zhuǎn)移酶G9a相互作用。然而,UHRF2與UHRF1也有著顯著的不同。UHRF2不能夠挽救Uhrf1缺失胚胎干細(xì)胞的DNA甲基化缺陷,因?yàn)閁HRF2沒有在細(xì)胞周期S期招募DNMT1至復(fù)制位點(diǎn)的能力。此外,由于UHRF2-SRA結(jié)構(gòu)域?qū)αu基化的結(jié)合偏好性,UHRF2被報(bào)道是羥甲基化DNA的特異性結(jié)合因子。如同UHRF1,UHRF2同樣被報(bào)道與腫瘤相關(guān)。但是對于UHRF2在腫瘤中表現(xiàn)的相關(guān)報(bào)道都比較淺顯且模糊。一些研究稱UHRF2表現(xiàn)出腫瘤抑制因子的特性,因?yàn)樗軌蚋蓴_細(xì)胞周期的進(jìn)程。而也有報(bào)道顯示,由于UHRF2的表達(dá)量在某些腫瘤中上調(diào),UHRF2可能具有潛在的原癌基因特性。關(guān)于UHRF2與腫瘤相關(guān)性的報(bào)道目前來說十分有限,UHRF2在腫瘤發(fā)生過程中的精確生物學(xué)功能,以及它是否如同UHRF1一樣可能參與轉(zhuǎn)移相關(guān)的過程,還需要進(jìn)一步的研究。轉(zhuǎn)移是惡性腫瘤的重要特點(diǎn),90%的癌癥死亡都是由于轉(zhuǎn)移導(dǎo)致。癌癥細(xì)胞的轉(zhuǎn)移是一個(gè)非常復(fù)雜的過程,這個(gè)過程中,細(xì)胞發(fā)生上皮-間質(zhì)轉(zhuǎn)化,從而獲得侵襲和轉(zhuǎn)移的能力。在上皮-間質(zhì)轉(zhuǎn)化的過程中,上皮細(xì)胞失去細(xì)胞-細(xì)胞間連接和細(xì)胞極性,獲得間質(zhì)樣細(xì)胞的特性,同時(shí)轉(zhuǎn)移和侵襲能力增強(qiáng)。上皮-間質(zhì)轉(zhuǎn)化是一個(gè)多級調(diào)控的過程,轉(zhuǎn)錄因子激活調(diào)節(jié)下游目標(biāo)蛋白的表達(dá)變化,從而擾動(dòng)細(xì)胞-細(xì)胞間連接、細(xì)胞極性、骨架結(jié)構(gòu)以及胞外基質(zhì)降解等多個(gè)生物學(xué)過程。雖然有關(guān)上皮-間質(zhì)轉(zhuǎn)化的研究近年有許多報(bào)道,但相關(guān)轉(zhuǎn)錄因子如何發(fā)揮調(diào)控機(jī)制依然需要進(jìn)一步的探索。蛋白質(zhì)組學(xué)技術(shù)是生物學(xué)研究中進(jìn)行大規(guī)模蛋白質(zhì)分析的強(qiáng)大手段。本實(shí)驗(yàn)室近年建立了一套快速非標(biāo)定量的流程,能夠在12小時(shí)的質(zhì)譜時(shí)間里鑒定8000個(gè)蛋白質(zhì)。這使得我們可以快速地進(jìn)行大量樣本的鑒定。同時(shí),我們還發(fā)明了一種轉(zhuǎn)錄因子富集技術(shù),能夠有效富集內(nèi)源性轉(zhuǎn)錄因子這種生物體中的低豐度蛋白,并進(jìn)行定量。將蛋白表達(dá)水平的檢測與轉(zhuǎn)錄因子-DNA結(jié)合活性的檢測相結(jié)合,使得我們能夠關(guān)聯(lián)轉(zhuǎn)錄因子的活性及其目標(biāo)蛋白的表達(dá)量變化。來自轉(zhuǎn)錄因子及蛋白表達(dá)水平的雙重信息的綜合分析,能夠?yàn)榈鞍卓赡馨l(fā)揮的生物學(xué)功能以及參與的信號轉(zhuǎn)導(dǎo)通路,提供重要的生物學(xué)線索。使用多重組學(xué)方式探索蛋白功能及機(jī)制,將是具有重要意義的揭示蛋白秘密的手段。在本篇文章中,為了探索UHRF2的功能,我們使用了蛋白表達(dá)水平的質(zhì)譜鑒定,轉(zhuǎn)錄因子活性變化的質(zhì)譜鑒定,IP-質(zhì)譜鑒定以及Ch IP-seq測序等多維度組學(xué)手段,檢測UHRF2在癌癥細(xì)胞系中過表達(dá)時(shí)引起的生物學(xué)變化。首先我們檢測了UHRF2在胃癌細(xì)胞系MKN74中過表達(dá)誘導(dǎo)的蛋白水平變化。在肽段1%FDR水平,共有7662個(gè)特異蛋白被質(zhì)譜檢測。經(jīng)過統(tǒng)計(jì)學(xué)分析,192個(gè)蛋白呈現(xiàn)上調(diào)變化,297個(gè)蛋白表現(xiàn)出下調(diào)變化。進(jìn)行GO分析后發(fā)現(xiàn),上調(diào)蛋白主要定位于細(xì)胞核、大分子復(fù)合物及胞質(zhì)內(nèi),而下調(diào)的蛋白質(zhì)則主要位于細(xì)胞-細(xì)胞間連接、基底膜以及內(nèi)膜系統(tǒng)中。鑒定結(jié)果顯示UHRF2抑制了許多上皮細(xì)胞表面標(biāo)志物的表達(dá),包括CDH1、JUP、TJP1、DSG2、INADL、SPINT2、CXADR、SPINT1以及TJP2;同時(shí),穩(wěn)定了一些包括p53在內(nèi)的重要核蛋白的表達(dá)。UHRF2過表達(dá)誘導(dǎo)的差異蛋白分析表明,UHRF2與細(xì)胞粘附及腫瘤轉(zhuǎn)移有重要相關(guān)性。為了進(jìn)一步探索UHRF2過表達(dá)誘導(dǎo)蛋白水平變化的驅(qū)動(dòng)因素,我們使用了TFRE富集加質(zhì)譜檢測的手段,檢測轉(zhuǎn)錄因子-DNA結(jié)合活性的變化。這使得我們能夠觀測到一組全蛋白鑒定無法檢測的低豐度轉(zhuǎn)錄因子。在肽段1%FDR水平,我們檢測到581個(gè)轉(zhuǎn)錄因子以及537個(gè)轉(zhuǎn)錄共調(diào)控因子。經(jīng)過統(tǒng)計(jì)學(xué)分析,其中17個(gè)轉(zhuǎn)錄因子及8個(gè)轉(zhuǎn)錄共調(diào)控因子因UHRF2過表達(dá)而出現(xiàn)DNA結(jié)合活性的增強(qiáng)。根據(jù)文獻(xiàn)報(bào)道,其中5個(gè)活性增強(qiáng)的轉(zhuǎn)錄因子被注釋為上皮-間質(zhì)轉(zhuǎn)化相關(guān)轉(zhuǎn)錄因子。這些分析表明轉(zhuǎn)錄因子-DNA結(jié)合活性的變化與蛋白表達(dá)水平的變化具有非常好的一致性,且都支持同一個(gè)模型:UHRF2過表達(dá)導(dǎo)致EMT轉(zhuǎn)錄因子的激活以及EMT相關(guān)蛋白的表達(dá)變化。結(jié)合組學(xué)鑒定提供的信息,為了進(jìn)一步驗(yàn)證UHRF2參與EMT過程,我們使用CRISPR-Cas9技術(shù)在惡性胃癌細(xì)胞系SGC7901以及BGC823中使用不同的引導(dǎo)RNA(g RNA)敲除UHRF2并進(jìn)行Transwell實(shí)驗(yàn)評估細(xì)胞轉(zhuǎn)移能力。與對照組相比,UHRF2敲除非常明顯地抑制了細(xì)胞遷移和侵襲能力。此外我們還發(fā)現(xiàn),UHRF2的缺失誘導(dǎo)SGC7901細(xì)胞發(fā)生了明顯的形態(tài)變化,由間質(zhì)樣細(xì)胞向上皮樣細(xì)胞轉(zhuǎn)變,同時(shí)細(xì)胞之間發(fā)生聚集。這些結(jié)果表明UHRF2對調(diào)控細(xì)胞轉(zhuǎn)移能力具有重要作用。我們使用UHRF2抗體及對照Ig G抗體進(jìn)行了Ch IP實(shí)驗(yàn)以尋找UHRF2與DNA結(jié)合的位點(diǎn),結(jié)果表明,UHRF2與CDH1的啟動(dòng)子區(qū)域有結(jié)合,可能作為一個(gè)轉(zhuǎn)錄共調(diào)控因子與EMT-TFs一起調(diào)節(jié)CDH1的表達(dá)。為了進(jìn)一步證實(shí)這個(gè)猜想,我們進(jìn)行了IP-質(zhì)譜鑒定實(shí)驗(yàn),以探尋UHRF2相互作用蛋白。結(jié)果表明,UHRF2與一些表觀調(diào)控復(fù)合體相結(jié)合,且與EMT轉(zhuǎn)錄因子TCF7L2有相互作用,進(jìn)一步提供了UHRF2參與EMT過程的證據(jù)。綜上所訴,在本篇文章中,我們證明了UHRF2作為一個(gè)轉(zhuǎn)錄共調(diào)控因子通過調(diào)節(jié)上皮-間質(zhì)轉(zhuǎn)化過程影響腫瘤細(xì)胞的遷移和侵襲能力。我們在胃癌細(xì)胞系中過表達(dá)UHRF2蛋白,然后進(jìn)行多維度的組學(xué)分析。全蛋白表達(dá)的鑒定結(jié)果提示UHRF2對細(xì)胞-細(xì)胞間連接具有抑制作用;轉(zhuǎn)錄因子-DNA結(jié)合活性的檢測表明UHRF2過表達(dá)引起EMT轉(zhuǎn)錄因子活性的升高;生物學(xué)實(shí)驗(yàn)證明敲除UHRF2能夠抑制腫瘤細(xì)胞的轉(zhuǎn)移和侵襲能力;Ch IP-seq及相互作用蛋白組表明UHRF2作為一個(gè)轉(zhuǎn)錄共調(diào)控因子,與EMT轉(zhuǎn)錄因子一同參與EMT過程的調(diào)節(jié)�？傊�,我們的研究揭示了蛋白UHRF2的生物學(xué)功能,同時(shí)為蛋白功能研究提供了強(qiáng)大而有效的新手段,即通過多重組學(xué)鑒定,綜合多個(gè)生物學(xué)層面的信息,獲得蛋白功能及相關(guān)信號通路的全面線索,進(jìn)而進(jìn)行生物學(xué)功能的驗(yàn)證。
[Abstract]:UHRF is a protein family with multiple domains for a group of protein characteristics, contains 4 members. Among them, the most studied UHRF1, UHRF1 was reported to play an important role in many biological processes, such as it can maintain DNA methylation of.UHRF2 DNMT1 mediated with sequence and domain structure similar to that of UHRF1. This structural similarity indicates the function between the two protein conserved. Like UHRF1, UHRF2 is also able to identify the hemi methylated DNA and methylated histones, in vitro was also demonstrated with DNMTs and histone methyltransferase G9a interaction. However, UHRF2 and UHRF1 have different.UHRF2 is not significant can save the Uhrf1 deletion of DNA methylation defects in embryonic stem cells, because UHRF2 is not in the S phase of the cell cycle to recruit DNMT1 replication sites ability. In addition, due to the UHRF2-SRA domain of the hydroxylated binding preference of UHRF2 was reported Is the specificity of hydroxymethylated DNA binding factor. Like UHRF1, UHRF2 is also reported associated with cancer. But for the reported expression of UHRF2 in tumors are relatively simple and fuzzy. Some studies showed UHRF2 characteristics of tumor suppressor, because it can interfere with cell cycle progression and also. Reported that, due to the expression of UHRF2 in some tumors increased, UHRF2 may have potential. The characteristics of the original cancer gene on UHRF2 and tumor related reports at present is very limited, UHRF2 in tumor biology process can work accurately, and whether it is like UHRF1 may be involved in processes related to the transfer, also need further study transfer is an important feature of malignant tumors, 90% of cancer deaths are due to metastasis result. Metastasis of cancer cells is a very complex process, the process of cell Epithelial mesenchymal transition, resulting in the invasion and metastasis ability. In epithelial mesenchymal transition process, epithelial cells lose cell-cell junctions and cell polarity, obtain the characteristics of mesenchymal cells, the metastasis and invasion ability. Epithelial mesenchymal transition is a process control the transcription factor activator expression regulate downstream target proteins, thereby perturbing cell-cell junctions, cell polarity, skeleton structure and extracellular matrix degradation in many biological processes. Although the epithelial mesenchymal transition research in recent years there are many reports, but the transcription factors related to how to play the regulation mechanism still needs further exploration. Proteomics is a powerful technique for protein analysis by means of large-scale biological research laboratory in recent years. This has established a fast non quantitative process, can be in 12 hours of mass spectrometry Time in the identification of 8000 proteins. This allows us to quickly identify a large number of samples. At the same time, we also developed a transcription factor enrichment technology, can effectively enrich low abundance proteins of endogenous transcription factor in the organism, and quantitatively. The protein expression level of -DNA and transcription factor binding activity detection the combination, so that we can change the expression of target protein activity and associated transcription factors. Comprehensive analysis from the transcription factor and protein expression level of dual information, to biological functions of proteins may play and participate in the signal transduction pathway, provide important clues to the biology. Using recombinant protein function and mechanism of science exploration that would be of great significance to reveal the protein secret means. In this article, in order to explore the function of UHRF2, we make use of the The expression level of protein identification by mass spectrometry, mass spectrometry identification of transcription factor activity, IP- and Ch IP-seq sequencing identified multi-dimensional group by means of biological changes caused by detecting the expression of UHRF2 in cancer cell lines. At first we examined the UHRF2 in gastric cancer cell line MKN74 in protein expression level changes induced in. Peptide 1%FDR levels, a total of 7662 specific protein by mass spectrometry. After statistical analysis, 192 proteins showed an increasing change, 297 proteins exhibited down-regulation changes. GO analysis found that the up-regulated protein mainly localized in the nucleus, macromolecular complexes and the cytoplasm, and down regulated proteins are mainly located in the cell - the connections between cells, basement membrane and membrane system. The identification results show that UHRF2 inhibits many epithelial cell surface marker expression, including CDH1, JUP, TJP1, DSG2, INADL, SPINT2, CXADR, SPINT1 At the same time, stability and TJP2; the expression of.UHRF2 and some important nuclear proteins including p53 protein induced analysis showed that overexpression of UHRF2 with cell adhesion and tumor metastasis have important correlation. In order to further explore the expression of UHRF2 protein level changes induced by driving factors, we use the TFRE enrichment plus mass spectrometry method. The changes of the activity of transcription factor -DNA. Combined detection of low abundance transcription factor which allows us to observe a whole group of protein identification cannot be detected. At the peptide level of 1%FDR, we detected 581 transcription factors and 537 transcriptional co regulation factor. Through statistical analysis, of which 17 transcription factors and 8 transcriptional co regulation the enhancement factor by UHRF2 overexpression and DNA binding activity. According to the literatures, the transcription factor activity was enhanced 5 notes for the EMT related transcription factors . these analyses show that the transcription factor -DNA binding protein activity change and expression has very good consistency, and will support the same model: UHRF2 leads to activation of the EMT transcription factors and the expression of EMT related protein expression changes. Combined with the group identification information provided, in order to further verify the UHRF2 in EMT the process, use the guide of different RNA we use CRISPR-Cas9 SGC7901 in malignant gastric cancer cell lines and BGC823 (g RNA) and UHRF2 knockout Transwell experimental assessment of metastasis ability. Compared with the control group, UHRF2 knockout very significant inhibition of cell migration and invasion. In addition, we also found that the occurrence of morphological changes obviously SGC7901 cells induced by UHRF2 deletion, change from mesenchymal cells into epithelioid cells, and between cells aggregation. These results suggest that the regulation of UHRF2 on cells Has an important role in metastasis. We use the UHRF2 antibody and G antibody control Ig Ch IP experiment to find the combination of UHRF2 and DNA loci, the results show that the promoter region of UHRF2 and CDH1 combination, expression may act as a transcriptional co regulation factor together with EMT-TFs regulation CDH1. To further confirm this conjecture. We conducted IP- mass spectrometry experiments, to explore the interaction protein of UHRF2 and UHRF2. The results show that some epigenetic regulation of complex combination and interaction with EMT transcription factor TCF7L2, provides further evidence of UHRF2 involved in the EMT process. To sum up, in this article, we show that UHRF2 as a a total of transcription regulatory factor by regulating epithelial mesenchymal transition process affecting tumor cell migration and invasion. The overexpression of UHRF2 protein in gastric cancer cell lines, and then multi dimension Proteomic analysis of total protein expression. The identification results showed that UHRF2 of cell-cell connection has inhibitory effect; transcription factor -DNA binding activity assay showed that UHRF2 overexpression increased EMT transcription factor activity; biological experiments show that knockdown of UHRF2 can inhibit the invasion and metastasis of tumor cells; Ch and IP-seq interacting protein group show UHRF2 as a transcriptional co regulation factor regulating transcription factor EMT to participate in the EMT process. In conclusion, our study reveals the biological function of UHRF2 protein, while the protein function research provides a powerful and effective, that is through the reorganization and identification, multi level biological information obtained comprehensive clues protein function and signal pathway, and then verify its biological function.

【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：Q51

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