巴美肉羊发情期血清生殖激素和卵巢microRNAs的鉴定及功能分析
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摘要
繁殖性状是养羊业的重要经济性状之一,增加绵羊每胎产羔数是降低生产成本、提高生产效率的有效措施,具有重要意义。绵羊产羔数的多少受排卵数的影响,而卵泡发育是一个极其复杂且高度协调的过程,受到来自下丘脑、垂体和卵巢的内分泌、旁分泌/自分泌因素和多种生长因子的精密调节。然而到目前为止,卵泡的发育、成熟、排卵及造成排卵数差异的分子机制还未完全明了。近年来发现的microRNAs在机体生长发育、分化、代谢和疾病等许多生物过程发挥作用,其在哺乳动物生殖中的作用也逐渐受到重视。本研究以巴美肉羊为实验对象,采用ECLIA和miRNA microarray技术,从生殖内分泌激素和microRNAs两个层面入手,研究巴美肉羊发情期生殖激素变化规律和卵巢microRNAs表达谱,分析经产单、双羔母羊血清生殖激素分泌和卵巢microRNAs表达差异,初步探讨造成绵羊产羔数差异的因素及其分子调控机理。
     1、巴美肉羊发情期血清生殖激素变化规律及其与产羔数关系研究
     采用ECLIA技术,分析4种生殖激素FSH、LH、E2和P4在单、双羔巴美肉羊发情期外周血中的分泌规律和特点,探讨生殖激素与产羔数的相互关系。结果表明:
     (1)血清中FSH和LH均呈脉冲式分泌,单、双羔母羊血清FSH在发情后的1h都出现一个峰值(P<0.001),LH在发情后的12~24h出现峰值;血清中E2和P4在单、双羔组间变化规律不同:单羔羊E2呈“V”字形变化趋势,双羔羊E2总体呈下降趋势;单羔羊P4呈上升趋势,双羔羊P4呈倒“V”字形变化趋势。
     (2)方差分析显示,双羔羊FSH水平在发情后1h极显著高于单羔羊(P<0.001),12h显著高于单羔羊(P<0.05);双羔羊LH水平在发情后12h极显著高于单羔羊(P<0.001),24h显著高于单羔羊(P<0.05)。结果表明,巴美肉羊产羔数增加可能与血清FSH和LH浓度升高有关。
     (3)血清中E2和P4各时间点的浓度水平,在单羔组和双羔组间羊均无显著差异(P>0.05),但这两种激素在单、双羔组间呈现不同的变化规律,其与巴美肉羊繁殖力关系有待进一步研究。
     2、巴美肉羊卵巢组织microRNAs表达研究及差异表达microRNAs的筛选、鉴定和特征分析
     (1)应用多物种miRNA芯片对3例产单羔母羊及3例产双羔母羊的卵巢组织进行miRNAs表达分析。结果,在检测的来自所有物种的miRNAs中,有5448个miRNAs在绵羊6个卵巢组织样本中共同表达,22个miRNAs在单羔组样本中特异表达,15个miRNAs在双羔组样本中特异表达。在检测的来自绵羊的103个miRNAs中,有47个miRNAs在6个样本中共同表达。
     (2)对来自绵羊的103个miRNAs进行差异表达分析。双羔绵羊与单羔绵羊相比,共获得卵巢组织差异表达miRNAs11个,其中上调表达4个(Fold Change≥2),下调表达7个(Fold Change≤0.5)。这些miRNAs可能与绵羊卵泡发育和产羔数多少有关。随机选择芯片结果中上、下调表达的基因oar-miR-381-5P和oar-miR-1185-5p,利用miRNA Real Time RT-PCR技术进行验证,结果表明miRNA芯片结果准确、可信。
     (3)生物信息学分析得知,筛选获得的11个差异表达miRNAs中,除oar-miR-544-5p与绵羊参考基因组无相似序列外,其余miRNAs均是位于绵羊18号染色体上的内含子miRNAs。分别利用2种方法(microT法和miRDB法)预测差异表达miRNAs的靶基因,取二者交集,共获得7个miRNAs的靶基因:oar-miR-370-5p、oar-miR-376b-5p、oar-miR-381-5p、oar-miR-412-5p、oar-miR-541-3p、oar-miR-544-5p和oar-miR-1185-5p,这些miRNAs分别预测获得115、71、1、5、8、135和23个靶基因。
     (4)靶基因GO注释结果表明:miR-376b-5p和miR-1185-5p的靶基因在细胞成分、分子功能和生物学过程的大部分分类中都有分布;结合已有文献,miR-376b-5p的靶基因IGF-1、DAZL、MTOR等和miR-376b-5p的靶基因AHR与哺乳动物的卵泡生长发育、生殖激素分泌等生殖过程密切相关,同时也说明miR-376b-5p和miR-1185-5p可能通过这些靶基因对哺乳动物生殖过程发挥调控作用。
Reproductive trait is one of most important economic traits in the sheep industry.It’s an effective measure to increase litter size per fetus to reduce production costs andincrease productivity, with important theoretical and practical significance. Sheep littersize is affected by ovulation rate. Follicular development is an extremely complex andhighly coordinated process, which is precisely regulated by the endocrine,paracrine/autocrine factors from hypothalamus, pituitary and ovary as well as manyother growth factors. So far however, the molecular mechanism of folliculardevelopment, maturation, ovulation and the reasons caused ovulation rate differences isnot fully understood. In recent years, microRNAs have been discovered to play a role inmany biological processes, such as body growth, differentiation, metabolism anddisease, and its role in mammalian reproduction is also gradually taken seriously. Inthis study, two aspects were researched about reproductive endocrine hormone andovarian microRNAs. The study performed ECLIA and miRNA microarray assay toresearch reproductive hormones change and ovarian microRNAs expression profileduring estrus of Bamei mutton sheep, and compare their differences betweensingle-bearing and biparous ewes, in order to discuss the factors and molecularregulation mechanism causing differences in sheep litter size.
     1. Research of serum reproductive hormone changes and their relationship withlitter size in Bamei mutton sheep during estrus
     Rules and characterization of4kinds of reproductive hormone FSH, LH, E2and P4were analyzed during estrus of single-bearing and biparous Bamei mutton sheep usingECLIA technology. The results showed that:
     (1) Serum FSH and LH were secreted in a pulsatile way. Concentration of serumFSH peaked at1h after estrus (P<0.001), and concentration of serum LH peak during12~24h after estrus; Serum E2and P4appeaed different changing rules betweensingle-bearing and biparous groups: in single-bearing group, E2showed a "V" typechanging trend, while in biparous group, E2showed a downward changing trend; P4showed an upward changing trend in single-bearing group, but showed an inverted "V"type changing trend in biparous group.
     (2) Variance analysis showed that, serum FSH level in biparous ewes was extreme significantly higher than that of single-bearing ewes at1h after estrus(P<0.001), andwas significantly higher than that of single-bearing ewes at12h after estrus (P<0.05);serum LH level in biparous ewes was extreme significantly higher than that ofsingle-bearing ewes at12h after estrus (P<0.001), and was significantly higher thanthat of single-bearing ewes at24h after estrus (P<0.05). This indicated that, increase inBamei mutton sheep litter size may be associated with raised serum FSH and LHconcentration.
     (3) Serum E2and P4levels at different time points showed no significant differencebetween single-bearing and biparous group (P>0.05), but the two hormones showeddifferent changing rules between the two groups. Their relationship with Bamei muttonsheep fecundity remains to be further studied.
     2. MicroRNAs expression profiling and differentially expressed microRNAsscreening, identification and characterization in ovarian tissue of Bamei mutton sheep
     (1) Multiple species miRNA microarrays were applied to3cases of single-bearingewes and3cases of biparous ewes to analysis ovarian miRNAs expression. The resultsshowed that, in all the detected miRNAs, there were5448miRNAs expressed in6ovarian samples. Among them,22miRNAs were specifically expressed insingle-bearing samples, and15miRNAs were specifically expressed in biparoussamples. In103detected miRNAs from sheep, there were47miRNAs expressed in6ovarian samples.
     (2) Differential expression analysis was performed on the103miRNAs from sheep.Compared with single-bearing ewes, biparous ewes contained11differentiallyexpressed miRNAs in the ovarian tissue, of which4miRNAs were up-regulated (FoldChange≥2),7miRNAs were down-regulated (Fold Change≤0.5). These miRNAs maybe related to sheep follicular development and litter size. Up-regulated geneoar-miR-381-5P and down-regulated gene oar-miR-1185-5p were randomly selected tovalidate the accuracy of the microarray using miRNA Real Time RT-PCR technology.The results showed that, miRNA microarray results were accurate and credible.
     (3) Bioinformatics analysis indicated that, the11differentially expressed miRNAs,except for oar-miR-544-5p which had no similar sequence with sheep reference genome,were all intron miRNAs located in sheep chromosome18. Target genes of thedifferentially expressed miRNAs were predicted using two different methods (microTand miRDB), then took the intersection, and finally obtained a total of target genes of7miRNAs: oar-miR-370-5p, oar-miR-376b-5p, oar-miR-381-5p, oar-miR-412-5p, oar-miR-541-3p, oar-miR-544-5p and oar-miR-1185-5p, these miRNAs obtained115,71,1,5,8,135and23target genes, respectively.
     (4) GO annotation results of partial target genes showed that: the target genes ofmiR-376b-5p and miR-1185-5p were distributed in most functional classifications ofthe cell component, molecular function and biological process. Referring to the existingliteratures, the target genes of miR-376b-5p, such as IGF-1, DAZL, MTOR et al, andtarget gene of miR-376b-5p such as AHR were closely related to mammalianreproductive process such as follicular growth and development, reproductive hormonesecretion. At the same time, this also indicated that miR-376b-5p and miR-1185-5p mayplay important roles in the regulation of mammalian reproduction through these targetgenes.
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