2. 吉林农业大学, 长春 130118;
3. 吉林省野生动物救护繁育中心, 长春 130119;
4. 辽宁出入境检验检疫局技术中心, 大连 116001
2. Jilin Agricultural University, Changchun 130118, China;
3. Jilin Wild Animal Conservation and Breeding Center, Changchun 130119, China;
4. Liaoning Entry-Exit Inspection and Quarantine Bureau, Dalian 116001, China
miRNA是一类小的非编码RNA,广泛存在于动物的血清、血浆、唾液、初乳、腹膜液、精液、卵泡液等生物体液中,并在人和许多动物的生理(怀孕)和病理过程中起着关键作用。miRNA具有调节基因表达的功能,在基因表达中起着“微调”而不是“开关”的作用,并与多种细胞的代谢、分化、增殖和凋亡过程有关[1]。1997年Lo等[2]证实了母体血液中存在着部分的胎儿游离核酸,2000年Poon等[3]在母体血浆中检测到游离胎儿RNA,2008年Chim等[4]在人体血液中检测到妊娠特异性miRNA。同一物种血清中的胎盘miRNA水平在个体之间具有高度相似性[5]。由于血浆中存在的miRNA比mRNA更稳定[4],所以母体血浆中胎盘miRNA的含量可作为监测胎盘基因调控的重要依据。除了血液,胎盘亦是miRNA高度富集的器官之一[6],动物胎盘功能和动物妊娠与胎盘中的特异性miRNA簇具有十分重要的关系[7-9]。miRNA参与胚胎着床前子宫内膜的发育[10],调节炎症反应及免疫耐受相关基因在怀孕开始与维持过程中的表达。
1 妊娠相关的miRNA簇目前为止,已报道了600余种miRNA在人体胎盘的动态表达。胎盘miRNA可通过3个miRNA簇内的多种miRNA来表达,其中包括C14MC簇(chromosome 14 miRNA cluster, C14MC)、C19MC簇(chromosome 19 miRNA cluster, C19MC)以及miR-371-3簇[11-12]。特别是怀孕期间,妊娠相关胎盘miRNA簇的表达量在不断发生着变化[11, 13]。血液中的胎盘miRNA主要来源于绒毛滋养层。miRNA簇广泛存在于母体血液循环中,所以对动物妊娠诊断来说具有极大的应用潜力。
1.1 C14MC簇C14MC又被称为Mirg簇[14]、miR-379/miR-410簇或miR-379/miR- 656簇[15],包含约52个miRNA基因(产生63个成熟miRNA)[11-12, 16]。C14MC簇在真哺乳亚纲物种中是保守的,仅由母本遗传的等位基因(父本等位基因被甲基化)表达,并且主要在发育中的胚胎(头和躯干)和胎盘组织表达,也在滋养层细胞高度表达[17]。C14MC簇具有促进哺乳动物胎盘进化的作用[15]。
1.2 C19MC簇C19MC簇位于19号染色体上,是迄今为止人染色体上最大的miRNA基因簇之一。C19MC属灵长类动物的特异性miRNA家族,大鼠、小鼠以及狗的体内并没有发现该miRNA簇的同源物[18]。C19MC簇包括了46个miRNA(产生58个成熟miRNA)[17]。与C14MC簇类似的是,C19MC簇也位于印迹基因内,与C14MC相反的是,C19MC受17.6 kb上游CpG启动子区甲基化控制,仅由父本遗传等位基因表达[19]。印迹基因在细胞分化和命运的调控中具有重要作用,并且它们大都仅在胚胎期或胎盘组织中表达。C19MC的表达主要受生殖系统和胎盘的影响[13]。研究表明,C19MC簇在胚胎发育中具有重要的作用,妊娠早期许多外周体液中C19MC簇miRNA表达量升高[20]。
1.3 miR-371-3簇miR-371-3簇主要由hsa-miR-371a-3p、hsa-miR-372和hsa-miR-373-3p产生的6个成熟RNA组成的。miR-371-3簇共享着相同种子序列“AAG UGC”,并且该共享相同种子序列miRNA超家族还包括小鼠同源物簇miR-290-295[9]。miR-371-3簇位于与C19MC簇下游约25 kb的1 050 bp区域内[21]。与C14MC簇和C19MC簇类似的是仅在哺乳动物中高度保守,并且在胎盘中优先表达[22]。现已证明,miR-371-3簇是调节细胞增殖和凋亡必需的miRNA[23],因此对胚胎发育具有重要的作用。
对哺乳动物中人miRNA分析显示,C19MC簇、C14MC簇和miR-371-3簇在胎盘组织中高度表达,并且其表达随胎龄变化而变化[24]。C14MC簇和C19MC簇的水平在整个怀孕期间也不断地发生变化。C14MC簇在第一孕周的滋养层细胞中高度表达,但在妊娠中期减少。与C14MC簇相反,C19MC簇在妊娠前期表达较低,但在妊娠末期高度表达。妊娠终止后,受胎盘影响C14MC簇和C19MC簇妊娠相关的miRNA表达水平显著下降[11, 25]。胚胎与血液中的miRNA的变化反映并维持着动物机体妊娠进程,以miRNA鉴定为基础进行妊娠研究会是未来发展的大趋势。
2 miRNA与早期妊娠诊断早期妊娠诊断是哺乳动物繁殖管理的重要环节,其对于提高动物妊娠率尤为重要[26]。循环miRNA则对妊娠诊断具有潜在的预测性、特异性、敏感性,并且能以非侵入性的方式获得,其检测效率也相对较高[27-28]。Ioannidis和Donadeu[29]首次确定了牛早期妊娠期间血浆中miRNA的变化水平,发现了10个最丰富的miRNA,即bta-miR-133a、bta-miR-486、bta-miR-22-3p、bta-miR-19、bta-miR-191、bta-miR-423-5p、bta-miR-10b、bta-miR-142-5p、bta-miR-27b和bta-miR-30d,占总miRNA量的61%,其中,怀孕母牛第16天miR-133a表达水平比同期非怀孕小母牛高出7.4倍,并发现在怀孕16~24天期间miR-26a水平升高2倍以上。Ioannidis和Donadeu[30]进一步研究发现,最早可在牛妊娠第8天检测到miR-26a的水平明显增加,另外,第16天与第8天相比miR-101的水平也趋于升高。近期在猪和羊的研究中也发现,妊娠第20天时miR-26a在受孕卵巢中的表达水平出现增加[31-32]。在怀孕羊中还发现,miR-30c、miR-132、miR-379、miR-199a-3p和miR-320也出现差异表达。另有研究提出,bta-mir-140可作为早期妊娠诊断的分子生物标志物[33],这为研究者们通过miRNA进行早期妊娠诊断提供了新的依据。近年来,诸多学者提出通过对奶中miRNA谱高通量测序分析进行妊娠诊断也具有十分重要的意义[34]。miRNA广泛存在于血液[35]、唾液[36]、尿[37]和牛奶[38]等多种动物体液中,这些体液中的miRNA将来均有望成为研究妊娠诊断理想的分子标志物。
3 miRNA与妊娠相关疾病的关系miRNA除了在正常妊娠中发挥作用,其动态调节基因表达的能力也有助于妊娠相关病症的诊断,包括先兆子痫、异位妊娠、复发性流产、早产和胎儿宫内发育迟缓等[39]。虽然怀孕期间miRNA作为标志物的鉴定仍处于初期阶段,但现在已经筛选出了许多具有研究意义的miRNA。现阶段对于除人外的哺乳动物妊娠疾病与miRNA研究较少,以下主要讨论人常见怀孕异常引发的疾病与miRNA特征性关系。
3.1 miRNA与先兆子痫的关系先兆子痫(preeclampsia,PE)是指在哺乳动物妊娠后半期、分娩期或分娩后期出现高血压、蛋白尿或其他系统疾病的一种妊娠相关综合征[40]。PE在人中发病率高达8%[41], 然而PE在妊娠早期症状并不明显,很难进行诊断,因此寻找某种鉴定早期PE的方法至关重要。有研究表明,miRNA可参与PE的发病机制[42]。Ishibashi等[43]对人正常胎盘和PE胎盘之间的miRNA进行大规模高通量测序,筛选出了先兆子痫胎盘中显著上调的22种miRNA,为研究先兆子痫提供了有力依据。Yang等[44]研究发现,PE患者妊娠前3个月miRNA表达量有15个上调,7个轻度下调。其中严重PE患者血浆中的miR-24、miR-26a、miR-103、miR-130b、miR-181a、miR-342-3p和miR-574-5p表达量升高。Loux等[45]在孕马体内发现,与PE有关的miR-204b和hsa-miR-204表达上调。De Bem等[46]证明,妊娠奶牛血液中hsa-miR-26a水平增加与妊娠有关,这种miRNA与先兆子痫相关。先兆子痫的发生可能是由母体和胎儿-胎盘循环中的血管内皮功能障碍引起的,这种功能障碍会引起包括调节血管张力、膜转运功能、内皮存活或增殖、血管生成和代谢途径等相关miRNA表达量发生改变。
3.2 miRNA与异位妊娠的关系异位妊娠(ectopic pregnancy,EP)是指孕卵在子宫腔外着床发育的异常妊娠过程,也称“宫外孕”,孕妇发病率为1%~2%[47]。现阶段EP检测主要有两种方法,一种是阴道超声检查,但是经阴道超声不能准确地确定EP;另一种是通过检测母体血清中的人绒毛膜促性腺激素(HCG)和孕酮浓度,然而,通过血HCG和孕酮浓度对EP的诊断方法易产生假阳性和假阴性结果[48]。因此寻求一种快速、准确鉴定异位妊娠的方法至关重要。Zhao等[48]为了寻找可以更准确、敏感地鉴定人的异位妊娠生物标志物,比较了发生自发流产(spontaneous abortion, SA)和正常妊娠(normal pregnancy, NP)的EP患儿血清样本中妊娠相关miRNA的表达,结果显示,EP或SA与NP相比,miR-517a、miR-519d和miR-525-3p的表达量较低,而miR-323-3p表达量明显高于EP。Lu等[49]研究发现,SA和EP患者与正常孕妇相比,血清miRNA中的5种miRNA(miR-218、miR-233、miR-141、miR-873和miR-323)出现差异表达,并且miR-873作为单一标记具有最高的灵敏度,EP检测率高达61.76%。虽然对于miRNA异位妊娠研究较多,但现阶段利用miRNA来检测异位妊娠还不成熟,还需进一步筛选特异性标志物,通过HCG和孕酮与miRNA结合评估可以提高miRNA作为生物标志物的诊断性能,也可以提高异位妊娠的总体诊断效率。
3.3 miRNA与早产的关系人早产(premature delivery,PTD)分娩的定义为在妊娠37周之前的分娩。对于除人外的哺乳动物来说,妊娠时间各有差异,因此对于早产的时间定义也有所不同。研究发现,PTD患者中miRNA出现了差异表达[50-51]。Enquobahrie等[50]发现,人早产与miR-210和mir-223的含量增加相关。Pineles等[51]进行了miRNA微阵列分析,发现人绒毛膜中的39个miRNA在术前和早产组之间相比出现差异表达,miR-338、miR-449、miR-136和miR-199a表达出现下降。Mayor-Lynn等[52]分析了人早产和正常胎盘之间的miRNA表达谱,发现了20种差异表达miRNA,在早产孕妇胎盘中miR-15b、miR-181a、miR-210、miR-296-3p、miR-483-5p和miR-493等许多miRNA出现差异表达。Gray等[53]则证实,人母体血浆中miR-223表达升高与自发性早产相关,并认为miR-223有望成为早期预测自发性早产的miRNA生物标志物。另外,怀孕早期外周血中miRNA的定量分析对自发性早产的敏感和特异性预测也具有较高价值[54]。
4 miRNA与母乳的关系母乳中含有丰富的分泌型免疫球蛋白和双歧因子,具有提高动物免疫力、促进动物生长、降低动物幼崽发病率和死亡率的作用,对于新生哺乳动物幼崽来说至关重要。miRNA与催乳素生成途径相关,能够参与乳汁合成的生理过程[55]。现在有超过1 400种成熟的miRNA在人乳中表达[56],人乳中还含有丰富的免疫相关miRNA[56-57]。牛乳中的一些miRNA与神经系统通路有关,并可能介导大脑发育,如miR-118-2靶向了神经系统中丰富的蛋白神经元跨膜蛋白[58]。人乳中的一些miRNA还具有组织特异性[59],如miR-142-5p具有造血特异性[60]。人乳中miRNA还可能促进婴儿特定器官和组织的发育。此外,牛乳中miRNA与牛奶代谢途径相关,如let-7家族大量存在于牛奶中,参与了葡萄糖代谢,并可调节葡萄糖耐受量和胰岛素敏感性[58-59, 61]。另外,有研究发现,miRNA-148a在人乳中高度表达,并且miRNA-148a在白血病中表达较少,由此可推测,母乳中miRNA-148a等miRNA可能对儿童白血病具有保护作用[62]。值得注意的是,牛乳成分(包括miRNA)的昼夜变化可能对幼畜胃肠昼夜节律性的建立和调整有益[59]。
5 展望众多研究表明,miRNA与妊娠过程中的胚胎发育、妊娠疾病诊断及产后哺乳存在一定的关系。现阶段miRNA参与妊娠的多数功能是通过表达模式推测的,但尚未在多数哺乳动物中进行细致的功能研究,并且大都是通过采取部分组织或体液进行检测,并不一定能完全反映其在动物体内的正常生理水平。若miRNA作为怀孕功能验证的诊断工具,其快速精确的诊断特点对妊娠来说是不可或缺的,未来将miRNA应有到妊娠诊断时要注重对其稳定性进行深入探究。随着互联网技术和生物学检测手段的不断发展,miRNA在哺乳动物妊娠过程中的调控功能也会逐渐明晰,必将助力于畜牧与医药行业的发展。
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