近年来，竞争性内源RNA(competing endogenous RNAs，ceRNA)机制成为研究热点，即不同RNA分子间通过竞争小RNA(microRNA，miRNA)以阻断其对靶基因的抑制，因此，这些ceRNA也称为miRNA分子海绵(miRNA sponge)。2011年，Cesana等[1]发现长非编码RNA可作为ceRNA调控基因表达；同年, ceRNA作用机理假说也试图解释RNA分子间如何通过miRNA反应元件(microRNA response elements，MRE)进行“交流”[2]。近年来, 不同物种(包括病毒、植物、小鼠和人类)的相关研究表明，ceRNA可能代表了一个普遍的基因调控层面，其不仅可由非编码RNA介导，还能赋予mRNA编码蛋白质以外的功能[3]。研究表明，ceRNA信号受细胞环境、MRE数量、miRNA活性、ceRNA与miRNA间亲和力等众多因素影响。miRNA活性取决于自身表达丰度、亚细胞定位及miRNA相对靶点丰度(relative target site abundance，TA)，miRNA偶联的RNA间丰度还会相互影响[4]。因此，ceRNA信号的变化会在其调控网络中级联放大，影响上千个基因的表达[5]。并且，ceRNA调控网络并不只是信号的串联，而是包含分子本身的浓度控制、作用元件的调节、细胞环境影响的庞大调控系统。然而，ceRNA信号间的串扰、分子间定量关系、作用效率等问题在很大程度上仍不明晰。虽然环状RNA(circular RNA，circRNA)和长链非编码RNA(long non-coding RNA，lncRNA)等均可作为ceRNA，但circRNA是相对更为有效的ceRNA分子，因为其在进化过程中稳定且保守，可使ceRNA信号在不同组织中传导。本文就ceRNA调控机制的影响因素以及circRNA通过ceRNA途径调控畜禽重要经济性状的研究进展进行综述。
1 ceRNA调控机制影响因素ceRNA信号是以miRNA为核心的基因沉默现象，且是一种普遍的、在进化上保守的细胞调控途径[6]。ceRNA所包含的MRE数量、miRNA和ceRNA丰度、miRNA-RNA间分子亲和力等影响ceRNA活性的因素对维持生理稳态至关重要(图 1)。
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a.共享MRE的ceRNA可协同抑制靶基因丰度；b.ceRNA结合miRNA至其浓度降至阈值后释放，以充分抑制关键靶基因的表达；c.7 nt和8 nt的种子序列丰度低但具高亲和力，6 nt种子序列丰度高但低亲和力 a. ceRNAs sharing MREs can collaboratively suppress target gene abundance; b. ceRNAs bind miRNAs until their concentration drops to a threshold and then release them to fully suppress expression of target genes; c. 7 nt and 8 nt seed-matched sequences have low abundance but high affinity, 6 nt seed-matched sequences have high abundance but low affinity 图 1 ceRNA机制的影响因素 Fig. 1 The factors affecting the ceRNA mechanism |
MRE是位于靶mRNA与miRNA特异性结合的序列，通常导致靶点降解从而抑制靶基因的表达，转录本中包含的多个MRE可同时抑制多个靶基因的表达[7]，因此RNA分子间存在共享MRE的现象。事实上，大多数ceRNA包含1~10个MRE[8]，circRNA CDR1as(cerebellar degeneration-related 1 antisense)上有近70个miR-7结合位点[9]。由于共享的MRE将不同的ceRNA信号串联，因此MRE被共享的次数越多其串扰调控效应越强；而非共享MRE对ceRNA信号间的互作影响可忽略不计[10]。有研究表明，在IFN-α1基因家族间形成了一个ceRNA网络，IFN-α家族的反义IFN-α7/-α8/-α10/-α14/-α17亚型与4个mRNA亚型(IFN-α8/-α10/-α14/-α17)共享MRE位点参与拮抗miRNA-1270，竞争性地调节IFN-α1的mRNA水平[11]。由于体细胞碱基对突变、单核苷酸多态性(single nucleotide polymorphism，SNP)、染色体易位、转录融合、选择性剪接等情况会影响MRE的结合效率[3]，因此, 有研究报道可借助生物信息学手段对MRE突变的影响进行预测[12]。
1.2 miRNA和ceRNA丰度miRNA活性受其自身丰度和MRE在转录组内的相对数量(即TA)的影响[13]。Figliuzzi等[14]认为, ceRNA调控网络中只有处于易感状态的ceRNA才能对miRNA干扰作出反应，并显著地减弱ceRNA信号间的互作强度。在包含CDR1as的正常细胞中引入已被验证的靶标miR-7时，CDR1as水平在细胞外泌体中显著下调，而在细胞中略有上调，表明circRNA作为ceRNA在一定程度上受miRNA水平变化的调节[15]。ceRNA对miRNA的抑制受阈值的限制[2]。当miRNA不断与ceRNA结合至其浓度降至阈值，ceRNA释放使miRNA表达迅速升高，使ceRNA信号被短暂抑制，以充分抑制关键靶基因的表达[16]。定量研究证实，在每个肝细胞中添加1.5×105个MRE位点时开始观察到抑制现象，此阈值超过了任何内源性靶点的生理水平，因此单个ceRNA的表达变化很难影响miRNA分子或其他靶点的表达[17]。但ceRNA和miRNA等摩尔质量时，ceRNA信号的活性可达到最佳状态[10, 14]。因此，miRNA丰度可能对ceRNA信号传导效率起主导调控作用，且几乎不受ceRNA丰度的影响；而ceRNA可通过间接调控miRNA丰度诱导ceRNA信号传导。
1.3 miRNA与RNA分子间亲和力ceRNA的亲和力越高竞争miRNA的能力越强[18]，即使在ceRNA浓度较低时，高亲和力ceRNA仍可以其高活性与miRNA有效结合，再逐渐扩散到亲和力较低的位点[19]。同样地，具有高亲和力的miRNA靶点越少，抑制效果也越显著，而此时对其余靶点的影响几乎可以忽略不计[8]。亲和力主要取决于miRNA靶基因上MRE和miRNA种子区间的匹配度，在哺乳动物细胞中，大多数miRNA与其靶RNA是不完全互补的，受SNP、选择性剪接等因素的影响[20]，因此MRE核苷酸组成的不同，对靶RNA的抑制程度也并不相同，例如6 nt的种子序列具有低亲和力但高丰度，而7 nt和8 nt的种子序列具有高亲和力但低表达丰度[21]。MRE的简并性也导致与miRNA结合后ceRNA不会立即被降解，因此比完全互补的序列能更有效地发挥分子海绵作用[22]。
2 circRNA作为ceRNA调控畜禽重要经济性状近年来，对circRNA的深入研究丰富了人们对ceRNA信号的认知。大多数circRNA由编码蛋白质的外显子生成，并通过下游剪接供体反向共价连接上游剪接体环化形成[23]，这种结构使其在进化过程中稳定且保守，因此，circRNA可能成为比其他非编码RNA更为有效的ceRNA分子[24]。近年，circRNA在肌肉发育、脂肪沉积等重要经济性状形成的分子机制研究中大量被发现(图 2)。
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图 2 调控畜禽经济形状的ceRNA网络图 Fig. 2 A map of the ceRNA network for regulating economic traits of animals |
肌肉生长发育过程受蛋白编码基因和非编码RNA的精细调控，circRNA在肌肉组织中大量富集使其迅速成为肌肉生长调控网络的研究热点[25]。畜禽肌肉组织转录组测序生物信息学结果显示，差异表达的circRNA主要富集在糖酵解/糖异生、氨基酸生物合成、丙酮酸代谢等与细胞增殖、生存和分化等生物学过程，亲本基因显著汇集到JNK、AMPK、AKT、FoxO、mTOR、IGF1R等与生长发育显著相关的信号通路中[26-28]。
以牛的成肌细胞为例，circACTA1通过竞争性结合miR-199a-5p和miR-433激活丝裂原活化蛋白激酶11(MAP3K11)、丝裂原活化蛋白激酶7(MAP2K7)以及JNK信号通路，抑制成肌细胞的增殖、促进分化和凋亡过程[29]；circCPE通过结合miR-138抑制FOXC1的表达，circUBE2Q2和circFUT10共同吸附miR-33a，抑制牛成肌细胞的增殖，促进成肌细胞的凋亡[30-32]。不同的是，circTTN-miR-432-IGF2和circHUWE1-miR-29b-AKT3信号可通过介导AKT通路激活，促进成肌细胞的增殖和分化[33-34]。circINSR的调控路径是多样的，不仅可以通过circINSR-miR-34a-Bcl-2/CyclinE2信号抑制成肌细胞的增殖和凋亡，还可通过circINSR-miR-15/16-CCND1/Bcl-2/FOXO1/EPT1信号促进成肌细胞和前脂肪细胞的形成和增殖[35-36]。在家鸡上也陆续证实了一批通过ceRNA机制参与成肌调控的circRNA。如circCCDC91通过调控miR-15家族的多个成员，与circSVIL-miR-203-c-JUN/MEF2C/STAT1、circHIPK3-miR-30a-3p-MEF2C途径共同促进成肌细胞的增殖和分化[37-39]；circRILPL1-miR-145-IGF1R、circPTPN4-miR-499-3p-NAMPT信号，可以激活下游MAPK和AKT信号通路促进成肌细胞的发育[40-41]。circMGA-miR-144-5p-FAP信号可抑制成肌细胞增殖，促进肌管的形成[42]。家鸡骨骼肌卫星细胞中差异表达的circTAF8侧翼内含子序列中包含8个与肌肉发育和胴体肌肉重量相关的SNPs[43]，但这些SNPs是否对circTAF8成环或与MRE的结合有关还有待进一步深入研究。山羊的成肌细胞中包括CDR1as-miR-27a-3p-ANGPT1、circUSP13-miR-29c-IGF信号通路[44-45]，分别抑制和促进成肌细胞的分化过程。Cao等[46]给仔猪体内注射circMYLK4，发现其显著提高了慢肌标记基因的mRNA和蛋白水平，促进氧化型肌纤维(慢肌)形成。以上研究表明，circRNA介导的ceRNA调控网络对成肌细胞的生长发育具有重要调控作用。
2.2 circRNA作为ceRNA调控畜禽脂肪细胞的发育家畜脂肪组织转录组测序结果显示, circRNA参与了大量与脂肪发育相关的ceRNA调控网络[47-48]。如在猪和牛的脂肪细胞中脂肪沉积相关基因PPAR家族成员PPAR-α、PPAR-γ和产生的环状转录本circPPARα、circPPARγ分别通过circPPARα-miR-429、circPPARγ-miR-200b/miR-92a-3p-YY1信号途径促进脂肪细胞分化，抑制细胞增殖和凋亡[49-50]；circFUT10通过结合与繁殖性状密切相关的miRNA-let-7c抑制脂肪沉积相关基因PPARGC1的表达，促进脂肪细胞的增殖[51]。Zhang等[52]对牛不同时期脂肪细胞(前脂肪细胞、分化前脂肪细胞和成熟脂肪细胞)的转录组测序发现, circRNA大量表达于白色脂肪中，且近10%线性转录本也同时能够生成circRNA；进一步分析差异表达的circRNA中有80%与亲本基因表达水平相关性极高，在畜禽中验证了circRNA可能对亲本基因表达具有潜在的调控作用。鸭的脂肪细胞中也鉴定到circPLXNA1-miR-214-CTNNB1信号[53]。综上，circRNA可作为ceRNA参与调控脂肪细胞发育过程。
2.3 circRNA作为ceRNA调控动物乳腺上皮细胞发育和乳合成不同乳产品中差异表达的RNA(differentially expressed RNAs，DERs)文库构建促进了对泌乳性状具有重要调控作用circRNA的筛选[54]，小尾寒羊泌乳高峰期和非泌乳期乳腺组织样本中鉴定到差异表达circRNA，其中上调的有40个，下调的有1个，并从中预测到与乳腺发育相关的多个miRNA结合位点[55]。夏季和冬季奶牛的血样及乳样中发现19个上调和19个下调的circRNA[56]。研究报道circ006258-miR-574-5p-EVI5L信号可促进山羊乳腺上皮细胞生长和乳合成[57]。circEZH2-miR378b-LPL/CD36信号可促进牛乳腺上皮细胞的增殖，抑制其凋亡[58]。
2.4 circRNA作为ceRNA调控家畜卵泡和胚胎发育miRNA被广泛报道参与卵泡发育和闭锁调控[59]，circRNA作为miRNA海绵在动物繁殖过程中也发挥着重要作用。利用RNA测序技术分析不同繁殖力山羊群体卵泡期和黄体期卵泡中circRNA的表达情况，发现56个miRNA可以靶向192个DERs，包括miR-133家族(miR-133a-3p和miR-133b)、miR-129-3p和miR-21等对山羊的繁殖性状有重要影响的miRNA[60]。在山羊子宫内膜基质细胞中，circ9110-miR-100-5p-HOXA1信号可激活PI3K/AKT/mTOR和ERK1/2通路，促进子宫内膜基质细胞的增殖，有利于胚胎着床[61]；而子宫内膜上皮细胞中可通过circ8073-miR-34/miR-34-CEP55信号激活RAS/RAF/MEK/ERK/PI3K/AKT/mTOR通路抑制子宫内膜上皮细胞凋亡[62]。猪的卵巢颗粒细胞中可通过circANKHD1-miR-27a-3p/miR-142-5p-SFRP1和circINHA-miR-10a-5p-CTGF通路促进颗粒细胞的增殖[63-64]，而circ013267-miR-113-THBS1信号通路可促进鸭颗粒细胞的凋亡[65]。在健康猪卵泡中高表达的circSLC41A1，不仅可以通过circSLC41A1/miR-9820-5p/SRSF1途径促进卵泡颗粒细胞凋亡，通过生物信息学手段预测其还具有编码小肽的潜能[66]。另外体内试验证明，在猪卵丘细胞和卵母细胞中circARMC4以发育阶段特异性大量动态表达，通过体内注射其干扰siRNA导致仔猪染色体排列严重受损，并显著抑制早期胚胎发育[67]。
3 总结与展望对于非编码RNA调控网络ceRNA机制已作为一种较为成熟的信号传递途径，circRNA作为新的分子海绵，其高度保守性和稳定性更有利于ceRNA信号在不同组织中传导。circRNA中含有的多个MRE也可以实现ceRNA通路间的串扰，通过级联放大效应影响成百上千个ceRNA转录本的翻译。综上，circRNA在畜禽肌肉发育、脂肪沉积等重要经济性状形成的分子机制研究中大量被发现，但ceRNA通路间信号串扰的定量关系在很大程度上是未知的。因此，利用分子生物学算法以及新一代测序技术定量确定ceRNA的影响因素如何调控信号的传导或许是有待深入的研究方向。
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