發(fā)布時間：2018-05-11 02:25

  本文選題：溫度馴化 + 斑馬魚　； 參考：《上海海洋大學(xué)》2017年博士論文

【摘要】：環(huán)境溫度對生物的影響貫穿其整個生活史,包括生長、發(fā)育、繁殖、運動等多個重要的生物學(xué)過程。有氣象預(yù)測顯示由于全球變暖引起的極端高溫和由于北極冰蓋融化引起的寒潮將會頻繁侵襲我國。魚類生活在水環(huán)境中,水溫的變化對魚類的行為和生理生化活動影響巨大。極端溫度會使水產(chǎn)養(yǎng)殖業(yè)遭受重大的損失,使養(yǎng)殖魚類品質(zhì)下降或?qū)е麓竺娣e死亡。因此,研究溫度對魚類的影響就顯得至關(guān)重要。斑馬魚是一種重要的水生生物模型,具有拼接完整的基因組和可信度較高的基因注釋結(jié)果,可以滿足轉(zhuǎn)錄組、甲基化組等高通量測序數(shù)據(jù)分析的需要。近年來的研究結(jié)果對斑馬魚在低溫下的調(diào)控網(wǎng)絡(luò)有比較透徹的概述,同時發(fā)現(xiàn)了斑馬魚與羅非魚耐寒能力差異的分子機制。為我們選擇以斑馬魚作為研究對象奠定了堅實的基礎(chǔ)。近年來多項研究表明,生物體在弱于極端溫度的條件下,將會產(chǎn)生溫度馴化效應(yīng),使其耐受極端溫度的能力上升。另外有一些研究表明環(huán)境因素對生物體產(chǎn)生的影響可以持續(xù)很長的時間,甚至?xí)绊懫浜蟠纳婺芰�。然而這些研究工作主要集中在植物領(lǐng)域,對動物尤其是魚類的研究還比較少。因此,研究模式魚類——斑馬魚對溫度馴化的響應(yīng)機制就顯得至關(guān)重要。為了從多角度探究斑馬魚對溫度馴化的響應(yīng)機制,我們分別設(shè)計了三個實驗進行研究。首先,將斑馬魚ZF4細胞(正常培養(yǎng)溫度28°C)進行短期低溫馴化(18°C/5d)和長期低溫馴化(18°C/30d),探究在沒有神經(jīng)調(diào)節(jié)和激素調(diào)節(jié)的情況下,魚類細胞本身是否能夠獲得溫度馴化效應(yīng)。實驗發(fā)現(xiàn),將常溫(28°C)、短期馴化(18°C/5d)、長期馴化(18°C/30d)的ZF4細胞放入細胞致死低溫(10°C/3d)后,通過細胞存活率檢測和alamar blue還原性檢測實驗發(fā)現(xiàn),不管短期馴化和長期馴化的ZF4細胞的耐低溫能力都增強,說明其都獲得了溫度馴化效應(yīng)。利用MeDIP-seq的方法研究常溫(28°C)、短期馴化(18°C/5d)、長期馴化(18°C/30d)的ZF4細胞的甲基化的狀態(tài)。研究發(fā)現(xiàn)寒冷壓力可以改變ZF4細胞DNA甲基化模式,短期低溫馴化后DNA甲基化的水平增加,而在長期低溫馴化后DNA甲基化的水平有所恢復(fù),且稍稍低于對照組。通過分析找到了1024個低溫馴化后啟動子區(qū)域發(fā)生明顯改變的基因,并對這些基因做了GO富集和KEGG富集分析,結(jié)果顯示短期低溫馴化后參與葉酸合成通路的相關(guān)基因的啟動子區(qū)域發(fā)生了顯著的欠甲基化,由于葉酸可以作為5mC的甲基供體,因此推測葉酸合成通路的激活可能與短期馴化后整體甲基化水平升高有關(guān)。利用MeDIP-qPCR和BSP驗證生物信息分析得到的差異甲基化區(qū)域(DMRs),結(jié)果顯示MeDIP-qPCR和BSP的實驗結(jié)果與MeDIP-seq的測序結(jié)果基本相符。結(jié)果顯示,在沒有神經(jīng)調(diào)節(jié)和激素調(diào)節(jié)的條件下,斑馬魚細胞本身就可以對溫度馴化產(chǎn)生反應(yīng)。其次,為了研究溫度馴化是否能夠?qū)Π唏R魚產(chǎn)生持續(xù)的影響,并進一步探究產(chǎn)生持續(xù)性影響的分子機制。我們將斑馬魚受精卵分別放入不同胚胎發(fā)育溫度(22°C,27°C,32°C)中發(fā)育出膜,簡稱TE22、TE27、TE32,然后于常溫(27°C)下飼養(yǎng)8個月,以BS-seq的方法檢測各組斑馬魚成魚肌肉中DNA甲基化水平。通過分析gene、peseudogene、lincRNA、CGI、miRNA、rRNA及其上下游2Kb區(qū)域的甲基化狀態(tài)發(fā)現(xiàn),在gene body區(qū)域可以觀察到TE32的甲基化水平稍微高于TE22和TE27,而在上游和下游2K的區(qū)域,TE32的甲基化水平稍微低于TE22和TE27,在CpG島區(qū)域,TE27的甲基化水平略高于TE22,而TE32的甲基化水平最低。在miRNA和rRNA區(qū)域并沒有看到甲基化水平明顯降低的區(qū)域,但是其本身的甲基化水平變化比較劇烈。methylKit分析發(fā)現(xiàn),TE22和TE27、TE32和TE27之間存在大量DMCs位點,并且差異甲基化位點在每個染色體上比例大致相同。DMRs分析發(fā)現(xiàn)TE22 vs TE27之間的差異甲基化區(qū)域(DMRs)為1915個,其中超甲基化區(qū)域為990個,欠甲基化區(qū)域為925個。TE32 vs TE27之間的差異甲基化區(qū)域(DMRs)為2646個,其中超甲基化區(qū)域為1506個,欠甲基化區(qū)域為1140個。結(jié)果顯示,斑馬魚不同胚胎發(fā)育溫度(22°C,27°C,32°C)可以導(dǎo)致斑馬魚成魚的肌肉中特定區(qū)域的甲基化水平發(fā)生變化,證明溫度馴化可以對斑馬魚肌肉的DNA甲基化狀態(tài)產(chǎn)生持續(xù)性的影響。最后,為研究斑馬魚中低溫馴化效應(yīng)是否能夠遺傳,將在常溫(27°C)下飼養(yǎng)6個月的32對斑馬魚分成兩組,每組16對,一組繼續(xù)在常溫(27°C±0.5°C)下飼養(yǎng),編號TA27,另一組放置于低溫(22°C±0.5°C)下飼養(yǎng),編號TA22,馴化時長為4個月。分別配對TA27和TA22兩組斑馬魚,在產(chǎn)卵后的30min內(nèi)收集受精卵,放入培養(yǎng)皿中,將TA27組和TA22組的受精卵分為兩份,分別放置于27°C與20°C,統(tǒng)計四個培養(yǎng)皿中受精卵的出膜率,評估斑馬魚受精卵的低溫耐受能力。分別取TA27、TA22斑馬魚卵巢和在低溫20°C處理0h、2h、4h、6h、8h的受精卵,進行轉(zhuǎn)錄組測序,進而進行差異表達基因、GO和KEGG分析,并對表觀酶類的表達水平進行分析。結(jié)果發(fā)現(xiàn)經(jīng)過22°C馴化的斑馬魚的后代在致死溫度下(20°C)可以正常發(fā)育,并順利完成卵裂期,進入下一發(fā)育時期。而未馴化的斑馬魚在低溫下,會導(dǎo)致卵裂異常的表型,例如卵裂時細胞間隙過大、出現(xiàn)兩個分裂球,更有甚者會出現(xiàn)卵破碎的現(xiàn)象。將非馴化組斑馬魚所產(chǎn)的卵置于常溫下發(fā)育一定時間,再放置于低溫下,可以發(fā)現(xiàn)在常溫發(fā)育3h以內(nèi)的受精卵不能完成胚胎發(fā)育,而在常溫發(fā)育3.5h以后的受精卵則可以順利完成胚胎發(fā)育,進而出膜。這證明胚胎發(fā)育的前三個小時是易受到溫度影響的敏感期,而對親代的低溫馴化可以使其所產(chǎn)的受精卵度過這段時期,正常完成卵裂。GO富集分析顯示大量與信號通路激活、細胞間黏連的相關(guān)的生物學(xué)過程被激活。涉及大量與離子相關(guān)的生物學(xué)過程,例如離子通道活性、鈣離子結(jié)合、鈣離子通道復(fù)合體。涉及較多信號傳導(dǎo)相關(guān)的生物學(xué)過程,例如G蛋白偶聯(lián)受體活性、G蛋白受體信號通路、細胞間的信號傳導(dǎo)、信號傳導(dǎo)活性、Rho蛋白的信號傳導(dǎo)。涉及細胞移動和固著等過程,例如細胞固著、細胞移動、細胞生長等過程。與生長繁殖有關(guān)的過程,例如,成纖維細胞生長因子受體信號通路、細胞因子受體結(jié)合、干細胞分化、發(fā)育的負調(diào)節(jié)作用、胚胎器官發(fā)育等過程。KEGG富集分析發(fā)現(xiàn)鈣離子信號通路富集程度較高。GPCR信號通路可以調(diào)控Ca~(2+)信號通路的激活。由此可以進一步推測GPCR信號通路首先感知溫度降低,然后通過IP3影響Ca~(2+)信號通路,使Ca~(2+)信號通路激活。因此,斑馬魚低溫馴化下產(chǎn)生的耐寒能力可能就是通過激活Ca~(2+)信號通路而產(chǎn)生的。通過對多種組蛋白修飾相關(guān)酶類的表達量的統(tǒng)計分析,發(fā)現(xiàn)多種賴氨酸的甲基化和去甲基化酶類表達量發(fā)生了顯著的變化,證明還有其他表觀標(biāo)記參與了低溫馴化的過程。結(jié)果顯示,溫度馴化效應(yīng)可以遺傳給下一代,推測這個現(xiàn)象與GPCR調(diào)控下的Ca~(2+)通路有關(guān)。
[Abstract]:The impact of environmental temperature on life throughout its whole life history, including growth, development, reproduction, and sports, and other important biological processes. Weather forecasts show that the extreme heat caused by global warming and the cold wave caused by the melting of the Arctic ice cover will frequently attack China. The behavior and physiological and biochemical activities of the class are greatly affected. Extreme temperatures can cause the aquaculture industry to suffer major losses and cause the quality of fish to decline or cause large areas of death. Therefore, it is essential to study the effects of temperature on fish. Zebrafish is an important aquatic biological model, with a complete genome and credible splice. The results of high degree gene annotation can meet the needs of high flux sequencing data analysis, such as the transcriptional group and the methylation group. The recent research results have a thorough overview of the regulation network of zebrafish at low temperature. At the same time, we found the molecular mechanism of the difference in the cold tolerance of zebrafish and tilapia. Studies have laid a solid foundation. In recent years, a number of studies have shown that living organisms will produce temperature taming effects under extreme temperatures and increase their ability to tolerate extreme temperatures. In addition, some studies have shown that the effects of environmental factors on organisms can continue for a long time, and may even affect their offspring. However, these studies are mainly concentrated in the plant field, and there are few studies on animals, especially fish. Therefore, it is very important to study the response mechanism of model fish, zebrafish, to the temperature domestication. In order to explore the response mechanism of zebrafish to temperature domestication from multiple angles, we have designed three facts respectively. First, a short term low temperature acclimatization (18 degree C/5d) and long term low temperature domestication (18 degree C/30d) of zebrafish ZF4 cells (normal culture temperature 28 C) were carried out to investigate whether the fish cells could obtain temperature domestication in the absence of nerve regulation and hormone regulation. After a long tamed (18 C/30d) ZF4 cell was put into a cell lethal low temperature (10 degree C/3d), the cell survival rate and the Alamar Blue reducibility test showed that the low temperature tolerance of the ZF4 cells, regardless of the short-term domestication and the long-term domestication, showed that the temperature acclimation effect was obtained. The normal temperature (28 degree C) was studied by the MeDIP-seq method. The methylation status of ZF4 cells in short-term domestication (18 C/5d) and long-term acclimatization (18 C/30d) showed that cold pressure could change the DNA methylation pattern of ZF4 cells, and the level of DNA methylation increased after short term low temperature domestication, and the level of DNA methylation after long term low temperature domestication was recovered, and slightly lower than that of the control group. 1024 genes which have obviously changed in the promoter region after 1024 low temperature acclimation have been enriched and analyzed by KEGG enrichment. The results showed that the promoter region of the related genes involved in the folic acid synthesis pathway was significantly under methylation after the short term low temperature domestication, as folic acid could be used as the methyl donor of 5mC, thus speculating on the leaves Activation of acid synthesis pathway may be associated with elevated level of overall methylation after short-term domestication. Using MeDIP-qPCR and BSP to verify the differential methylation area (DMRs) obtained by bioinformatics analysis, the results show that the experimental results of MeDIP-qPCR and BSP are basically consistent with the sequencing results of MeDIP-seq. The results show that there is no neuromodulation and hormone regulation. Under the conditions, zebrafish cells themselves can react to temperature domestication. Secondly, in order to study whether temperature acclimation can have a sustained effect on zebrafish and further explore the molecular mechanism that produces persistent effects, we develop zebrafish fertilized eggs in different embryonic development temperatures (22 C, 27 C, 32 C). Membrane, called TE22, TE27, TE32, and then fed at normal temperature (27 degree C) for 8 months. The methylation level of DNA in the muscle of zebrafish fish was detected by BS-seq method. The methylation status of gene, peseudogene, lincRNA, CGI, miRNA, rRNA and its upper and lower regions could be observed. Higher than TE22 and TE27, and in the upstream and downstream 2K regions, the methylation level of TE32 is slightly lower than TE22 and TE27. In CpG island region, the methylation level of TE27 is slightly higher than TE22 and TE32 methylation level is the lowest. In miRNA and rRNA regions, there is no visible region of methylation level, but its own methylation levels are compared. Severe.MethylKit analysis showed that there were a large number of DMCs sites between TE22 and TE27, TE32 and TE27, and the difference methylation sites on each chromosome were roughly the same as.DMRs analysis found that the difference methylation region between TE22 vs TE27 (DMRs) was 1915, of which the hypermethylation region was 990, and the under methylation region was 925.TE32. The difference methylation area (DMRs) was 2646, in which the hypermethylation area was 1506 and the methylation area was 1140. The results showed that the different embryonic development temperature (22 C, 27 degree C, 32 C) of zebrafish could lead to the change of the methylation level in the specific region of the muscle of zebrafish. It was proved that the taming of the zebrafish could be used to the zebrafish muscle. The DNA methylation status of meat has a continuous effect. Finally, in order to study whether the effects of low temperature acclimatization in zebrafish can be inherited, 32 pairs of zebrafish for 6 months at normal temperature (27 C) are divided into two groups, each group is 16 pairs. One group continues to be kept under the normal temperature (27 C + 0.5 degrees C) and TA27, and the other is kept under low temperature (22 [C + 0.5 [C]). The number of TA22 and taming for 4 months. Two zebrafish groups of TA27 and TA22 were paired respectively. The fertilized eggs were collected in the 30min after spawning. The fertilized eggs of the TA27 and TA22 groups were divided into two portions, respectively, and placed in 27 C and 20 degree C, respectively, to calculate the film rate of the fertilized eggs in four Petri dishes, and to evaluate the low temperature tolerance of the zebrafish fertilized eggs. The ovaries of TA27, TA22 zebrafish and the fertilized eggs of 0h, 2h, 4h, 6h and 8h were treated at 20 degrees C at low temperature, and the transcriptional group was sequenced, then the differentially expressed genes, GO and KEGG analysis were carried out, and the expression levels of the epigenetic enzymes were analyzed. The results showed that the offspring of zebra fish after 22 degree C domestication could develop normally at the lethal temperature (20 degrees C). The undomesticated zebrafish can cause abnormal cleavage at low temperature, such as the oversize of the cleavage, the emergence of two cleavage balls, and the breakage of the eggs. The eggs produced by the non domesticated zebra fish are placed at normal temperature for a certain time and then placed under low temperature. It is found that the fertilized eggs within the normal temperature of 3H can not complete the embryo development, while the fertilized eggs after the normal temperature of 3.5H can successfully complete the embryo development and then produce the membrane. This proves that the first three hours of the embryo development are susceptible to the temperature influence, and the relative low temperature domestication can pass the fertilized eggs of the embryos. During this period, the analysis of normal complete cleavage.GO enrichment analysis showed that a large number of biological processes associated with signaling pathway activation and intercellular adhesion were activated. Many biological processes related to ion related, such as ion channel activity, calcium ion binding, calcium ion channel complex, involving many signal transduction related biological processes, such as G protein coupling receptor activity, signal transduction of G protein receptor, signal transduction between cells, signal conduction of signal, signal transduction of Rho protein, processes involving cell migration and fixation, such as cell fixation, cell movement, cell growth, and other processes related to growth and reproduction, such as fibroblast growth factor receptor signaling pathway, Cell factor receptor binding, stem cell differentiation, negative regulation of development, and embryo organ development,.KEGG enrichment analysis found that high concentration of calcium signaling pathway.GPCR signaling pathway can regulate the activation of Ca~ (2+) signaling pathway. Thus, it is further conjectured that the GPCR signaling pathway first decreases the perception temperature and then affects the IP3 pathway. The Ca~ (2+) signaling pathway activates the Ca~ (2+) signaling pathway. Therefore, the cold tolerance produced by zebrafish may be produced by activating the Ca~ (2+) signal pathway. By statistical analysis of the expression of a variety of histone modified enzymes, the methylation of several lysine and the expression of demethylation enzymes have been found. Significant changes have shown that there are other apparent markers involved in the process of low temperature acclimation. The results show that the temperature acclimation effect can be inherited to the next generation, which is related to the Ca~ (2+) pathway under the GPCR regulation.

【學(xué)位授予單位】：上海海洋大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：Q953

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