miR-194a MEDIATES DIETARY VITAMIN D3 IN THE JAK-STAT IMMUNE PATHWAY OF YELLOW CATFISH (PELTEOBAGRUS FULVIDRACO)
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摘要: 为了研究miRNA如何介导饲料维生素D3在黄颡鱼(Pelteobagrus fulvidraco)JAK-STAT通路中调节免疫应答的机制, 选择黄颡鱼幼鱼为主要研究对象, 设计了3组维生素D3浓度分别为1120、3950和16600 IU/kg的饲料, 开展了为期12周养殖实验, 养殖实验结束后进行鮰爱德华氏菌(Edwardsiella ictaluri)攻毒实验。对攻毒后的头肾和脾脏组织进行Illumina高通量测序, 筛选差异表达的miRNAs, 并对差异表达miRNAs进行靶基因的生物信息学预测和富集分析, 发现miR-194a的靶基因富集在JAK-STAT信号通路中; 进一步通过双荧光素酶报告基因实验验证了miR-194a对靶基因jak2a和tyk2具有靶向性调控的关系, 能够发挥对jak2a和tyk2的抑制作用; 通过体外巨噬细胞实验, 在细胞中同样检测到miR-194a可以响应培养基中不同浓度的活性维生素D3, 并对靶基因jak2a与tyk2同样发挥抑制作用; 通过进一步对靶基因在JAK-STAT通路中的下游基因表达检测, 发现随着JAK-STAT信号通路的激活, 抗炎症反应(AIR)因子及被其诱导激活的靶基因的表达量随着培养基中维生素D3浓度升高呈现上升趋势(P＜0.05), 炎症通路NF-κB通路被抑制(P＜0.05), 促炎因子IL-1β、IL-6和TNF-α等表达量显著下降(P＜0.05), 并且调节了巨噬细胞由M1型极化向M2型极化的转变(P＜0.05)。研究结果发现miR-194a能在体内体外实验中响应维生素D3的变化, 维生素D3通过促进miR-194a的表达, 负调控靶基因jak2a和tyk2, 并对JAK-STAT通路中的下游基因发挥间接作用, 阐释了miR-194a介导饲料维生素D3通过JAK-STAT信号通路调控黄颡鱼免疫应答的机制。
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关键词:
- 维生素D3 /
- miR-194a /
- JAK-STAT信号通路 /
- 免疫应答
Abstract: In order to investigate the mechanism about the regulation of immune response by miRNAs mediating feed vitamin D3 in the JAK-STAT pathway of yellow catfish (Pelteobagrus fulvidraco), three diets with vitamin D3 content at 1120, 3950 and 16600 IU/kg were designed for juvenile Pelteobagrus fulvidraco. The growth trial was carried out over a 12-week period, following by an Edwardsiella ictaluri challenge experiment. Illumina high-throughput sequencing of head kidney and spleen after bacteria challenge identified differentially expressed miRNAs. The target genes of miR-194a was enriched in the JAK-STAT pathway. The relationship between miR-194a and the possible target genes jak2a and tyk2 had been verified by a dual luciferase reporter gene assay, which indicated the inhibitory role of miR-194a on jak2a and tyk2. In vitro, miR-194a was also found to respond with different concentrations of vitamin D3, inhibiting the expression of the target genes of jak2a and tyk2. With the activation of the JAK-STAT signaling pathway, the expression of anti-inflammatory response (AIR) factors and the target genes were also activated, the NF-κB pathway was inhibited, with significant decrease in expression of pro-inflammatory factors IL-1β, IL-6 and TNF-α and the transformation of macrophages from M1-type to M2-type polarization was accelerated with the increasing of vitamin D3 concentration (P<0.05). In conclusion, the results of this study demonstrated that miR-194a could respond to different concentration of vitamin D3 in vivo and in vitro experiments. Dietary vitamin D3 up-regulated the expression of miR-194a, which negatively regulated the target genes of jak2a and tyk2, and exerted indirect effects towards the downstream genes in the JAK-STAT pathway, illuminating the mechanism of miR-194a-mediated regulation of immune response by dietary vitamin D3 through the JAK-STAT signaling pathway in Pelteobagrus fulvidraco.-
Key words:
- Vitamin D3 /
- miR-194a /
- JAK-STAT signaling pathway /
- Immune response
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图 1 头肾与脾脏组织非编码RNA的分类与注释
Figure 1. Classification and annotation of non-coding RNAs from cephalic kidney and spleen tissues
图 2 头肾与脾脏组织差异表达miRNAs散点图(Ⅰ区域为上调, Ⅱ区域为下调)
Figure 2. Scatter plot of differentially expressed miRNAs in head kidney and spleen tissues (Ⅰ zone represents up-regulation, Ⅱ zone represents down-regulation)
图 3 不同浓度组之间头肾与脾脏组织共表达的差异miRNAs(A为Diet2 vs. Diet 1, B为Diet 3 vs. Diet 1)
Figure 3. Differential miRNAs co-expressed in head kidney and spleen tissue between different concentration groups (A for Diet 2 vs. Diet 1, B for Diet 3 vs. Diet 1)
图 4 头肾组织中差异表达miRNAs的表达量
Figure 4. Expression of differentially expressed miRNAs in head kidney
图 5 头肾与脾脏差异表达miRNAs靶基因GO富集(A、B为头肾, C、D为脾脏)
Figure 5. GO enrichment of head kidney and spleen differentially expressed miRNAs target genes (A and B for head kidney, C and D for spleen)
图 6 头肾与脾脏差异表达miRNAs靶基因KEGG富集(A、B为头肾, C、D为脾脏)
Figure 6. KEGG enrichment of head kidney and spleen differentially expressed miRNAs target genes (A and B for head kidney, C and D for spleen)
图 7 miR-194a在jak2a和tyk2的3′UTR内的潜在结合位点
Figure 7. Potential binding sites for miR-194a within the 3′ UTR of jak2a and tyk2
图 8 miR-194a mimics和miR-194a NC转染后miR-194a表达量倍数变化
Figure 8. Fold change of miR-194a expression after miR-194a mimics and miR-194a NC transfection
图 9 miR-194a对jak2a(A), tyk2(B)重组质粒荧光素酶活性的影响
Figure 9. Effect of miR-194a on luciferase activity of jak2a (A), tyk2 (B) recombinant plasmid
图 11 靶基因通路下游基因mRNA的表达量
Figure 11. Expression of target genes at downstream of the pathway
图 12 通路负反馈因子和炎性因子mRNA的表达量
Figure 12. Expression of pathway negative feedback factor and inflammatory factor mRNA
图 13 巨噬细胞M1型极化标志物 mRNA的表达量
Figure 13. Expression of M1-type polarization marker mRNA in macrophages
图 14 miR-194a介导维生素D3调节JAK-STAT通路示意图
Figure 14. Schematic of miR-194a mediates vitamin D3 of the JAK-STAT pathway
表 1 实验饲料组成和营养成分
Table 1. Formulation and proximate composition of experimental diets
项目Item 饲料1 Diet 1 饲料2 Diet 2 饲料3 Diet 3 原料(%饲料干重) Ingredient (% dry matter) 血粉Blood meal 10 10 10 脱脂奶粉Skim milk powder 5 5 5 玉米蛋白粉Corn gluten meal 2 2 2 面粉Wheat flour 10 10 10 酪蛋白Casein 30 30 30 豆粕Soybean meal 10 10 10 菜粕Canola meal 10 10 10 大豆油Soybean oil 10 10 10 赖氨酸Lysine 1 1 1 蛋氨酸Met 0.1 0.1 0.1 氯化胆碱Choline Chloride 0.5 0.5 0.5 维生素C Vitamin C 0.5 0.5 0.5 三氧化二钇Yi2O3 0.1 0.1 0.1 抗氧化剂Antioxidant 0.02 0.02 0.02 矿物盐Mineral premix1) 2 2 2 无VD3维生素预混料Vitamin premix2) 0.5 0.5 0.5 维生素D3预混物Vitamin D3 premix3) 0.2 0.8 3.2 麸皮Bran 8.08 7.48 5.08 理论维生素D3 Theoretical value of Vitamin D3 (IU/kg) 1000 4000 16000 营养成分(%饲料干重)Proximate composition (% dry matter) 水分Moisture 5.45 5.23 5.55 粗蛋白Crude protein 47.60 46.44 46.12 粗脂肪Crude lipid 4.53 4.56 4.48 灰分Ash 3.30 3.47 3.37 钙 Calcium 0.26 0.23 027 总磷Total phosphorus 0.34 0.34 0.35 实测维生素D3 Detected value of Vitamin D3 (IU/kg) 1120 3950 16600 注: 1)矿物盐预混料Mineral premix (mg per kg diet): 氯化钠NaCl 198 mg; 硫酸镁MgSO4·7H2O 2995 mg; 硫酸钠Na2SO4 4560 mg; 硫酸钾K2SO4 4098.5 mg; 氯化钙CaCl2·2H2O 2340 mg; 硫酸亚铁FeSO4 499.5 mg; 乳酸钙Calcium lactate 700.5 mg; 硫酸锌ZnSO4·7H2O 70.6 mg; 硫酸锰MnSO4·4H2O 32.5 mg; 硫酸铜CuSO4·5H2O 6.2 mg; 硫酸钴CoSO4 0.2 mg; 碘化钾KI 0.6 mg; 麸皮bran 4498.4 mg; 2)无VD3的维生素预混物(广州市联鲲生物科技有限公司定制) Vitamin premix (Specially made by Nutriera; per kg diet): 维生素A Vitamin A 2750 IU,维生素E Vitamin E 25 IU; 维生素K3 Vitamin K3 5 mg; 维生素B1 Vitamin B1 10 mg; 维生素B6 Vitamin B610 mg; 维生素B12 Vitamin B12 10 mg; 尼克酸niacin 50 mg; 核黄素riboflavin 10 mg; 泛酸钙D-calcium pantothenate 25 mg;叶酸folic acid 5 mg; 肌醇inositol 50 mg; 抗坏血酸ascorbic acid 50 mg; 脱脂米糠bran 1757.43 mg. 3)维生素D3预混物(包膜饲料级别,由广州市联鲲生物科技有限公司提供)Vitamin D3 premix(Coated vitamin D3 was provided by Nutriera; 500000 IU/kg) 
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表 2 实验中的PCR反应所使用的引物序列
Table 2. Primers used for the PCR reaction in the present study
名称Name 序列 Sequence (5′—3′) miR-194a Forward GCGCGTGTAACAGCAACTCC miR-194a RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACCCACAT miR-192 Forward GCGCGATGACCTATGAATTG miR-192 RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACGGCTGT miR-122 Forward CGCGTGGAGTGTGACAATGG miR-122 RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACCAAACA miR-730 Forward GCGTCCTCATTGTGCATGCT miR-730 RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACACACAC miR-734 Forward GCGGTAAATGCTGCAGAATC miR-734 RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACCGGTAC miR-212 Forward CGCGCGTAACAGTCTACAGTC miR-212 RT primer GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACAGCCAT jak2a Forward CTGAGAGACAGAAAGCAAAGGAG jak2a Reverse GGTAATGAACACCGATGGAGAGT tyk2 Forward GTGCGGCTTGCTCAGATTA tyk2 Reverse GCATTCGTAACATATACTGTATAGGTTT xhol-jak2a aattctaggcgatcgctcgagCTGAGAGAC AGAAAGCAAAGGAGG jak2a-not Ⅰ attttattgcggccagcggccgcGGTAATGAACACCGATGGAGAGTT xhol-tyk2 aattctaggcgatcgctcgagGTAACAAATCGATCCATTCTGCTC tyk2-not Ⅰ attttattgcggccagcggccgcTTGCATTCGTAACATATACTGTATAGGTT jak2a突变Forward GTGTCacaatgGTTCGTCAGTTTCCATGATGACAT jak2a突变Reverse GACGAACcattgtGACACAATGCAAATTTAACTGAGATG tyk2突变Forward CAGTATAacaatgTGCCCACGTTTACAACATGTAGC tyk2突变Reverse GGGCAcattgtTATACTGTATAGGTTTAAGGCAGAAGAGTG
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表 3 实验中的PCR反应所使用的引物序列
Table 3. Primers used for the PCR reaction in the present study
名称
Name序列
Sequence (5′—3′)GenBank登录号
GenBank accession No.jak2a-F CTGAGAGACAGAAAGCAAAGGAG KP337350.1 jak2a-R GGTAATGAACACCGATGGAGAGT tyk2-F GTGCGGCTTGCTCAGATTA KP337354.1 tyk2-R GCATTCGTAACATATACTGTATAGGTTT stat3-F ATCGGAGGACCCCCTAACACG KP342388.1 stat3-R TCTTTAGGGATGTCGGGGACC stat4-F GAGACCTCAGATGGAAGAACAAG KP342391.1 stat4-R TCAGAGAGATGGGAATCAGAATA il-12-F ATCATTGTAGTTCCACGCCGA XM_021476743.1 il-12-R TGTAACAGCACCCTGAAAGCA bcl-3-F ATTTTGTGTCAGGCACGCAGA XM_027149518.1 bcl-3-R AAGTTGTTTGGGGATGGGGTA nfil3-F GCGTGATAGTCTCCGCTGTAAA XM_027141051.1 nfil3-R GGAGCCTCTGTTTGGTCTTTGT zfp36-F CAATCAGGTGAACTCAAGCCG XM_027172447.1 zfp36-R GGGGTGTTGGATGGAGAAGAT socs1-F CGCTCTTACACACGGAAAACC MH410161.1 socs1-R GAACGACTCCTTGCTTCCCATA socs3-F AGCGGCTTTTACTGGGACG MH497390.1 socs3-R CACTGCTGCCACCTTCACTGT p65-F AAAGAGCAACGATTCCACCAA MK645606.1 p65-R CGTTGCCCAGTTTGAGGTTAT jak1-F GCACGCTGGTGATTCCTGACTG KP318953.1 jak1-R CTCGCACTATGGCTCTGAAGAACG il-10-F AACAGTTGCTGCTCCTTCATTG KY218793.1 il-10-R AGATTTCAAAAGGTTTCTGGCAT il-1β-F CTGCTCAGCCTGTGTGTTTGGG XM_027139384.1 il-1β-R AGATGTGGAGCGGAGCCTTCG il-6-F CCTGCTCTCGCTCGGACTCTAC XM_027176013.1 il-6-R ACTTCTGGTCTGGAGCGTGAGC tnf-α-F CTGCACGCAGGAGCCTGAATC XM_027133763.1 tnf-α-R AAGTGCTGTGGTCGTGTCTGTG il-12b-F TTGTTGTGTCTTTATTCGTTGGC NM_001007108.1 il-12b-R AGTTGGGAGCAGTCACATTTTTT Il-21-F TTTCTGCTTATGTGTGTGTTGGC NM_001128574.1 Il-21-R TTTCTGTGTCTCTTGTGGTGTGC Il-22-F GATTACGCCAAAGGTGAAAAGA XM_027151712.1 Il-22-R GCAGGATTCAAAGAGGTAGTGG β-actin-F GGATTCGCTGGAGATGATG KM673246.1 β-actin-R TCGTTGTAGAAGGTGTGATG
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