畜牧兽医学报  2018, Vol. 49 Issue (10): 2063-2069. DOI: 10.11843/j.issn.0366-6964.2018.10.001    PDF    
长链非编码RNA在畜禽经济性状中的研究进展
杨兵1,2, 李晓凤2, 王昕1     
1. 西北农林科技大学动物科技学院, 杨凌 712100;
2. 铜仁职业技术学院, 铜仁 554300
摘要:长链非编码RNAs(long noncoding RNA,lncRNAs)是一类转录本长度>200 nt的非编码RNA(non-coding RNA,ncRNA),且广泛存在于动物、植物及微生物的细胞质和细胞核中。研究表明,LncRNA能够在染色质、转录和转录后水平调控基因表达,参与动物几乎所有的生命过程,例如繁殖、肌肉生长、脂肪沉积、毛囊生长、乳腺发育和泌乳等。本文就lncRNA的作用机制及其在畜禽经济性状研究中的现状进行了综述,旨在为lncRNA在畜牧业中的研究和应用提供理论依据。
关键词长链非编码RNAs    调控机制    畜禽    经济性状    
Research Progress of Long Noncoding RNA in Economic Traits of Livestock
YANG Bing1,2, LI Xiao-feng2, WANG Xin1     
1. College of Animal Science and Technology, Northwest A & F University, Yangling 712100, China;
2. Tongren Polytechnic College, Tongren 554300, China
Abstract: Long noncoding RNAs(lncRNAs), a kind of noncoding RNA transcripts with the length more than 200 nucleotides, widely exists in cytoplasm and nuclei of animals, plants and microbes. Studies have shown that lncRNAs can regulate gene expression at chromosomal, transcriptional and post-transcriptional levels. lncRNA plays a vital role in most life processes in animals, such as reproduction, muscle growth, fat deposition, hair follicle development, mammary gland development and lactation. This paper reviews the regulation mechanism and current research status of lncRNAs in livestock economic traits, which would provide theoretical basis and practical reference for the research and application of lncRNAs in animal husbandry.
Key words: long noncoding RNA     regulation mechanism     livestock     economic trait    

传统的基因调控研究主要是围绕蛋白编码基因。然而,在过去的十几年里,随着下一代测序技术的飞速发展,越来越多的证据表明,调节生物体复杂发育过程的主要是基因组中非编码部分[1]。研究发现,哺乳动物的基因组约70%被转录,但只有约2%转录产物具有编码蛋白功能,余下约98%被转录为非编码RNA(noncoding RNAs, ncRNAs),这意味着ncRNAs对复杂的生物体具有重要的调控作用[2-3]。ncRNA根据转录本的长度分为长链非编码RNA(long noncoding RNA,lncRNA)和小非编码RNA(microRNA)。lncRNA占ncRNA的80%,多由RNA聚合酶Ⅱ催化转录形成。与mRNA相比,ncRNA不具备典型的起始密码子、启动子保守区、终止密码子及开放阅读框等[4-5]。在过去很长时间里,lncRNA被看作是“转录噪声”,不被人们所重视[6]。近几年,随着lncRNA功能研究不断深入,愈来愈多具有生物学功能的lncRNA相继被证实。lncRNA能够在染色质、转录和转录后等水平调控基因表达,发挥生物学功能。研究表明,lncRNA具有诸多生物学功能,例如参与细胞增殖[7-8]、分化[9-10]和凋亡[11-12],促进成肌细胞分化和损伤诱导的肌肉再生[13]、脂肪沉积[14]、泌乳[15]、生殖[16]和免疫[17]等生命过程。本文就lncRNA的作用机制、生物学功能以及在畜禽重要经济性状研究中的现状进行综述,旨在为lncRNA在提高畜禽生产性能及动物分子育种中的研究及应用提供理论参考。

1 lncRNA的作用机制

作为近年来研究的热点之一,lncRNA一般被定义为转录本长度超过200 nt、不具有编码潜能的RNA分子[18]。根据lncRNA在基因组上相对于蛋白编码基因的位置,将lncRNA大致分为正义、反义、基因内、基因间、双向和重叠lncRNA等几种类型[19]

lncRNA是基因表达的重要调控分子之一,其功能复杂多样。根据其作用方式大致分为3类:一类是染色质水平,通过对染色质进行表观修饰调节基因表达;第二类是转录水平,通过改变介导基因表达调控相关因子及酶类的功能,从而调控基因表达;第三类是转录后水平,通过与编码基因或者miRNA结合,从而调节mRNA和miRNA的表达水平[20]

1.1 lncRNA在染色质水平的调控作用

细胞核来源的核糖核酸蛋白-lncRNA复合物参与染色质修饰,从而调控某些基因表达[21-22]。例如,哺乳动物X染色体失活特异转录因子(lncRNA Xist)控制着X染色体的失活[23];作为一个基因间lncRNA(long intergenic noncoding RNA, lincRNA),HOTAIR的5′端能够与多梳蛋白抑制复合物2(polycomb repressive complex 2, PRC2)结合,3′端与LSD1/CoREST/REST复合物结合,lincRNA HOTAIR通过募集组蛋白修饰酶,介导特定目标位点上的组蛋白修饰[24]

1.2 lncRNA在转录水平的调控作用

lncRNA的表达水平通常与反义编码基因或邻近基因的表达水平有关,但表达量较低[25]。与参与染色质修饰的蛋白相比,lncRNA不需要重新进入核中就可发挥调控功能[26]。lncRNA可以由增强子元件产生,具有增强子样的功能。产生的增强子样lncRNA(enhancer-like RNA, eRNA)可通过染色体开放性而促进基因的表达[27];lncRNA还能够作为转录阻遏物抑制其靶基因的表达或者作为转录因子,促进转录并调节基因的表达[28-29];此外,lncRNA还可促进染色质修饰和重塑复合体的组装,并协助募集到靶基因,从而激活或抑制基因的转录,如linc-RAM作为一个调控因子,通过增强MyoD基因的转录活性,促进MyoD-Baf60c-Brg1复合物的形成[30]

1.3 lncRNA在转录后水平的调控作用

lncRNA能够与其对应的编码基因或者miRNA结合,从而降解编码基因的mRNA水平。Su等[31]研究了人肝癌细胞中lncRNA HOTAIRFOXC1基因和miR-1的关系,结果表明,HOTAIR的过表达促进了肝癌细胞的增殖和肿瘤异种移植;FOXC1与HOTAIR的上游区域相结合,激活了lncRNA HOTAIR的表达,而且HOTAIR能够负向调控肝癌细胞中miR-1的表达。此外,研究还表明,HOTAIR的致癌活性部分是基于miR-1的负向调节。lncRNA作为竞争性内源RNA(ceRNA),通过与miRNA结合而降低miRNA的活性,间接上调miRNA相关靶基因的表达,如牛肌肉组织特异性lncMD,通过竞争性吸附miR-125b,释放对其靶基因IGF-2的抑制作用,导致IGF-2基因的表达水平升高,从而促进肌肉的分化[32]

2 lncRNA在畜禽经济性状中的研究进展

目前,关于lncRNA在畜禽经济性状形成机理方面研究的热度持续升高,从lncRNA的角度探究畜禽重要经济性状(例如繁殖、肌肉发育、泌乳和脂肪沉积等性状)的分子调控机制,对于提高动物的生产性能和进一步的育种工作具有重要的理论意义。

2.1 lncRNA在畜禽繁殖调控中的作用

已有的研究表明,lncRNA参与卵子成熟[33]、精子形成[34]、胎盘形成[35]、妊娠[36]、性腺激素应答[37]、胚胎发育[38]和性别决定等过程[39]。郭芹芹等[40]在培养液中添加3 mmol·L-1谷胱甘肽研究其对牛体外受精胚胎中lncRNA表达谱的影响,结果发现,在添加组和对照组之间差异表达的lncRNAs有59个,功能富集分析表明,这些lncRNAs参与生物黏附、生物调节、繁殖以及病毒繁殖等诸多过程。性别决定对于畜禽的某些限性性状来说具有重要的意义,Roeszler等[41]报道,lncRNA MHM可以调控鸡的胚胎发育和性腺发生,lncRNA MHM敲低可引起母鸡卵巢发育不对称以及公鸡睾丸DMRT1基因表达量降低,而DMRT基因家族的主要功能是参与性别决定与分化。此外,lncRNA通过参与FOXL2基因转录调控母山羊的性反转,影响山羊的性别决定[42]。Caballero等[43]在牛早期胚胎lncRNA测序的基础上,挑选了3个lncRNAs进行功能研究,结果表明,敲低这3个lncRNAs后,牛成熟卵母细胞的发育速度显著加快,囊泡显著增大(P < 0.05)。进一步对囊泡进行甲基化谱和转录组联合分析,发现这些lncRNAs参与了囊泡的存活,胚胎着床与母体子宫内膜发育协调作用。Wang等[44]采用RNA-Seq技术对怀孕第9、12和15天以及空怀期第12天约克夏母猪子宫内膜组织lncRNA的表达模式进行了全面分析,对各时期差异表达的lncRNA进行功能富集分析表明,一些lncRNA与胚胎着床过程有关,其中lncRNA TCONS_01729386和TCONS_01325501在胚胎附植前可能起着至关重要的作用;各时期差异表达的基因参与了蛋白质结合、细胞过程和免疫等过程,并在焦点粘连、Jak2-STAT、FoxO以及MAPK信号通路中富集。可见,lncRNA在动物的卵泡发育、妊娠及性别决定方面都具有重要的调控作用。

2.2 lncRNA在畜禽肌肉生长与发育中的作用

大量的研究表明,lncRNA调控肌细胞的细胞分化和细胞周期等过程[45-46]。在肌肉发育和分化过程中,肌源性分化因子MyoD基因是一个主要的转录因子。Guo等[45]通过定制的微阵列技术平台,分析了MyoD基因敲除后lncRNA的表达情况,结果发现,lncRNA-AK143003的表达水平与MyoD一致,该lncRNA作为负调控因子在骨骼肌细胞分化方面具有重要的作用。Xu等[46]研究发现,lncRNA H19在1周龄、1月龄、6月龄和36月龄公牛的骨骼肌中高表达,而且lncRNA H19的高表达是牛肌卫星细胞分化所必需的。lncRNA H19的敲除引起成肌抑制基因Sirt1/FoxO1的高表达,表明H19在肌肉形成过程中抑制了Sirt1/Foxo1的表达。Yue等[47]采用高通量测序技术对牛背最长肌、肩胛部肌肉、肋间肌和臀肌的RNA表达特性进行了分析,发现lncYYW在以上各组织中的表达量较高,而且在成肌细胞分化过程中,lncYYW的表达量逐渐增加。lncYYW的过表达增加了S期肌卫星细胞的数量,并上调了肌源性标记—肌生成素和肌球蛋白重链的表达。芯片分析结果表明,lncYYW在牛成肌细胞中正向调控生长激素1(growth hormone 1, GH1)及其下游基因AKT1和PIK3CD的表达。Jin等[48]证实,过表达lnc133b能够促进卫星细胞的增殖,lnc133b通过负向调控miR-133b的表达而间接调节FGFR1、PP2AC基因的表达,从而调控牛骨骼肌卫星细胞的增殖和分化。Xing等[49]为探究睾酮对猪肌肉发育的影响,对去势和未去势的淮南猪公猪屠宰性状进行了比较,并对背最长肌进行lncRNA测序分析,结果发现,去势显著降低了眼肌面积和瘦肉率,但是脂肪量增加;测序分析发现,背最长肌中有8 946个lncRNAs,包括6 743个基因间lncRNAs(LincRNAs),498个反义lncRNAs(anti-sense lncRNAs)和1 705个基因内lncRNAs(intronic lncRNAs)。这些lncRNAs中,385个在去势组和未去势组间差异表达,对其靶基因的功能分析表明,主要参与了雌激素受体信号通路、骨骼肌系统发育和功能等。Chao等[50]对不同产肉性能的绵羊骨骼肌进行lncRNA测序,结果发现了39个差异表达的lncRNAs,其中29个lncRNAs与肌肉发育、代谢、细胞增殖和凋亡有关。以上的研究表明,在多个物种的肌肉发育过程中,lncRNAs参与了成肌细胞的分化、增殖和凋亡等多个方面,但是其具体的调控机制仍待深入研究。

2.3 lncRNA在畜禽脂肪形成与沉积中的作用

脂肪是动物机体的重要组成成分,对于畜禽健康及其产品品质极为重要。郑竹清等[51]利用RNA-seq技术对山羊肌内前体脂肪细胞和成熟肌内脂肪细胞中差异表达的lncRNAs进行了分析,结果表明,29个lncRNAs在肌内脂肪细胞成熟前后显著差异表达,且这些lncRNAs在生长调节、细胞形态变化以及细胞分泌等方面发挥着重要作用。Li等[52]对体外培养的牛前体脂肪细胞和分化的脂肪细胞采用RNA-seq技术进行测序分析,发现了一个与脂肪分化相关的lncRNA(ADNCR),该lncRNA作为竞争性内源RNA结合miR-204而抑制成脂分化,进一步研究发现,miR-204能够靶向SIRT1基因,该研究丰富了脂肪分化的调控机制。Pang等[53]研究表明,猪前体脂肪细胞中lncRNA PU.1 AS通过与PU.1 mRNA结合形成复合物,阻止了PU.1 mRNA的翻译从而促进脂肪形成。Zhang等[54]采用RNA-seq技术分析了不同分化阶段的鸡前体脂肪细胞lncRNAs和mRNAs的表达特性,发现了1 336和1 759个差异表达的lncRNAs和基因,为进一步研究鸡的脂肪细胞分化提供了依据。Yu等[55]采用RNA-seq技术对陆川猪和杜洛克猪肝、肌肉和脂肪组织的lncRNAs和mRNAs差异表达情况进行了比较分析,发现在肝、肌肉和脂肪3个组织中特异表达的lncRNAs数量分别为386、349和336个,组织特异性表达的基因数分别为1 123、800和1 513个;对脂肪组织特异性表达的lncRNAs与脂肪相关的数量性状位点(quantitative trait loci, QTL)进行相关分析发现,275个lncRNAs位于13个脂肪相关的QTL区域,该结果为研究lncRNA调控脂肪沉积的机制提供了重要的理论依据。

2.4 lncRNA在畜禽毛囊生长周期及泌乳中的作用

Wang等[56]基于lncRNA、microRNA(miRNA)高通量测序技术和生物信息学分析,对陕北白绒山羊毛囊生长期和休止期差异表达的lncRNAs、mRNAs和miRNAs进行了分析,结果发现,1 108个lncRNAs、2 492个mRNAs和541个miRNAs在毛囊生长期和休止期差异表达。与休止期相比,1 388个基因、41个lncRNAs和15个miRNAs的表达量显著上调,而1 104个基因、157个lncRNAs和8个miRNAs的表达量显著下调;对差异表达lncRNAs的靶基因进行了顺式和反式作用分析,结果表明,LNC_000972、LNC_000503和LNC_000881附近有WNT3A、HOXC13等与毛囊周期相关的基因,提示lncRNA可能与邻近基因作用调控毛囊周期。此外,还发现miRNA-mRNA和miRNA-lncRNA存在相互作用,因此构建了3个内源性竞争RNA的lncRNA-miRNA-mRNA调控网络:miR-221-5p-lnc_000679-WNT3、miR-34a-lnc_ 000181-GATA3和miR-214-3p-lnc_000344-SMAD3,该研究为lncRNA调控毛囊周期性发育的分子机制提供了理论依据。

人及模式动物相关研究已表明,lncRNA参与哺乳动物的乳腺发育以及调控泌乳等过程[15, 57]。Zhang等[58]发现,过表达lncRNA ROR可增加乳腺干细胞的自我更新,通过对其功能的进一步研究,结果表明,lncRNA ROR在维持乳腺上皮细胞正常干细胞亚群中起着关键作用。由于家畜上对lncRNAs研究的起步较晚,因此关于lncRNA调控母畜泌乳及乳腺发育方面的研究报道较少。近年来,Tong等[59]利用生物信息方法,从5个牛乳腺RNA-Seq数据库中鉴定出了886个未知的基因转录本(UITs)。然后利用CPAT、CNCI、CPC和Hmmscan等软件组合,预测了它们的非编码潜力,并鉴定了184个lincRNAs。与Noncode2016数据库和国内动物长链非编码RNA数据库(ALDB, http://202.200.112.245/aldb/)比对,在牛乳腺中新发现了112个lincRNAs,其中36个lincRNA位于与牛奶性状相关的172个QTLs中,1个lincRNA位于临床乳房炎的QTL区域内。此外,他们利用LncTar预测了这些lincRNAs的潜在生物功能,并预测了10个lincRNAs的靶基因。进一步对lincRNAs靶基因的功能分析表明,这些lincRNA参与了防御反应、RNA磷酸二酯键水解、内切核苷酸的cAMP介导信号、氧化还原酶分子功能、细胞因子受体结合、蛋白质转运、溶酶体细胞组成部分等信号通路,该研究为lincRNA调控奶牛乳腺发育及对乳腺炎易感性的生物学功能提供了依据。

另外,lncRNA在疾病的发生和发展过程中发挥重要作用,因此lncRNA已成为疾病诊断和治疗的潜在生物标记和靶标[60]。Ma等[61]采用牛病毒性腹泻病毒(BVDV)感染Madin-Darby牛肾细胞系的方法,探究宿主抵抗牛病毒性腹泻病毒、牛病毒性腹泻病毒感染宿主的机制。他们选取感染后2、6和18 h的牛肾细胞系进行高通量测序,结果发现了1 236个差异表达的lncRNAs和3 261个差异表达mRNAs。lncRNA靶基因的功能分析结果表明,这些基因聚集于MHC Ⅰ类生物合成过程、正向调控肽类蛋白、自然杀伤细胞激活以及干扰素/β-受体结合分子等生物过程,提示在BVDV感染过程中,这些lncRNA参与调控牛的免疫反应。

3 展望

目前,lncRNAs在畜牧学科中的研究仍处于研究起步阶段,主要局限于发现和鉴定特定组织或发育阶段的lcnRNAs。随着现代分子生物学技术、新一代测序技术以及生物信息分析技术的快速发展,将会有更多新的lncRNAs在畜禽研究中被发现,用于指导畜禽生产实践、经济性状改良、疾病防控以及治疗等方面。但是如何更系统地、具体地研究lncRNAs在畜禽重要经济性状中的功能是接下来几年甚至十几年畜牧工作者需要解决的问题。

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