2017, Vol. 37文章信息
- 汤志雄, 苟德明.
- TANG Zhi-xiong, GOU De-ming.
- miRNA调控成肌分化的研究进展
- Research Progress on miRNA Regulation of Myogenesis
- 中国生物工程杂志, 2017, 37(10): 103-110
- China Biotechnology, 2017, 37(10): 103-110
- http://dx.doi.org/DOI:10.13523/j.cb.20171014
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文章历史
- 收稿日期: 2017-04-12
- 修回日期: 2017-06-22
miRNA是一类长度约为20~24个核苷酸的内源性微小RNA，主要通过结合靶基因mRNA的3′UTR，降解靶mRNA或阻止蛋白翻译，在转录后水平负调控基因的表达[1]。也有少量报道表明miRNA可结合到5′UTR或编码区[2-4]。miRNA在成肌分化中有极其重要的作用，引起了研究者的密切关注。通过Dicer敲除小鼠的研究发现，这些小鼠的骨骼肌发育不良，表现在骨骼肌数量显著降低，肌纤维数量减少，形态异常，肌源性细胞凋亡增加和成肌细胞死亡严重[5]，充分证明miRNA对肌肉发育的重要性。因此，本文将通过介绍肌肉特异表达的miRNA(myo-miR)和几个在肌肉发育中发挥重要作用的非myo-miR的功能，阐述miRNA参与成肌分化调控的最新研究进展。
1 骨骼肌的发育和成肌分化骨骼肌约占体重的40%，是人体的重要组成部分。如果骨骼肌发育出现异常将导致肌肉发生病变，如肌肉萎缩，肥大等疾病。因而，骨骼肌的发育问题被广泛而深入地研究。肌肉发育较为复杂，人类胚胎时期的骨骼肌生成主要包括以下几个步骤：(1)体节分化后形成含有肌源性前体细胞的生皮肌节；(2)前体细胞增殖和分化形成成肌细胞；(3)成肌细胞进一步增殖，随后分化和融合形成肌管；(4)最后，肌管成熟形成肌纤维[6]。
为保证正常的肌肉生长，形态和伸缩性，多种与细胞增殖、分化、连接和凋亡相关的基因参与其中，同时生肌调节因子MyoD1，Myf5，MyoG，Myf6，Mrf4和其它的转录因子如Pax3，Pax7和Mef2家族参与肌肉发育调控[7]。其中，MyoD1和Myf5通过促进肌源性前体细胞的增殖和分化调控骨骼肌的早期发育；MyoG在成肌细胞分化形成肌管时起重要作用；Myf6参与分化和细胞命运的决定[8]；Mrf4在胚胎后期肌肉发育时和体外成肌细胞分化，融合形成多核肌管时迅速上调[9]；骨骼肌祖细胞的特征之一是表达Pax3和Pax7，这些高表达Pax3和Pax7的肌原性祖细胞构成自我更新的细胞群体，对后续骨骼肌生长和卫星细胞形成极其重要，而卫星细胞是成体骨骼肌再生所必需的；开始肌细胞生成时，表达Pax3的细胞迁移到体节，将形成骨骼肌，随后Pax7将上调表达，它能在分化前下调Pax基因[10]。Mef2即肌细胞增强因子2，在骨骼肌、平滑肌以及心肌中高度表达，其主要作用是在肌肉发育过程中调控肌细胞的分化，影响分化过程中基因的转录[11]。由此可见，增殖和分化是研究成肌分化的重要生物学过程。
体外研究成肌分化常用的模型是C2C12小鼠成肌细胞，1977年由Yaffe和Saxel等建立；而体外研究成肌分化常用的是小鼠肌肉注射Cardiotoxin，心脏毒素(CTX)诱导的肌肉损伤和再生模型，可以用于研究体内的成肌分化[12]。
2 调控成肌分化的myo-miR越来越多的miRNA证明对肌肉发育有重要影响。这些miRNA中仅有几个是在肌肉中特异表达的，大部分是在组织内广泛表达。目前，myo-miR主要有miR-1，miR-133和miR-206。miR-1和miR-133在心肌和骨骼肌中都表达，而miR-206仅在骨骼肌中表达[13-14]。这些miRNA在肌肉发育中的调控作用被广泛而深入地研究，miR-1和miR-206的主要功能是抑制成肌细胞增殖，并促进其分化；miR-133的主要功能是促进成肌细胞增殖和抑制分化[15]。miR-208，miR-499和miR-486也被归为肌肉特异表达的miRNA。
2.1 miR-1，miR-206与成肌分化 2.1.1 通过调控miR-1，miR-206本身的表达，影响肌肉发育Igf1-Akt-Foxo3-miR-1通路可影响miR-1的表达，且直接通过Foxo3调控miR-1的启动子活性影响其表达[16-17]。Hmox1特异下调Lin28和Dgcr8，从而直接影响miR-1和miR-206的合成和加工[18]。Bmp2是TGF-β家族中的一员，通过抑制pri-miR-206的加工成熟负调控miR-206的表达[19]。Tardbp可与miR-1和miR-206结合从而影响它们与RISC的结合[20]。除了以上蛋白或因子的影响，miRNA自身的靶基因也调控其表达，从而形成调控环路。例如：(1) YY1抑制miR-1和miR-206的转录，而研究证明miR-1和miR-206均靶向YY1[21-22]；(2) Mef2能促进miR-1和miR-206的表达，Hdac4Hdac4和Notch3是Mef2的抑制因子，而miR-1和miR-206均直接靶向Hdac4Hdac4和Notch3，从而形成正向的反馈调控通路[23-24]；(3)与之相似，miR-1和miR-206均靶向Pax7，使其下调，随后Id2下调，使Myod1的表达上调，从而促进miR-1和miR-206表达，形成另一条正向的反馈调控通路[25-26]。
2.1.2 miR-1，miR-206靶向在肌肉发育中与增殖相关的基因miR-1和miR-206的靶基因中，许多都与增殖相关。例如Pax3和Pax7，在卫星细胞中，过表达miR-1和miR-206，细胞的增殖潜能受到抑制，而分化能力得到促进；相反，抑制miR-1和miR-206表达时，Pax3和Pax7蛋白水平上调，同时，卫星细胞的增殖能力得到促进而分化受到抑制[25, 27]。Pola1，负责细胞内DNA合成，是DNA聚合酶α中最大的亚基；miR-1，miR-206均靶向Pola1，导致DNA合成抑制，最终，细胞周期受到抑制[28]。miR-1，miR-206还能靶向抑制Ccnd1和Ccnd2，从而调控细胞周期，揭示miRNA在促进分化的细胞退出细胞周期的重要作用[29-31]。miR-1，miR-206靶向IGF信号通路中的几个重要蛋白，如miR-1靶向Igf1，Igfr，Hspa(HSP70)[17, 32]；同时，miR-206也靶向Igf1，特别地，Igfbp5是miR-206的靶基因，一个依赖于IGF调控的抑制骨骼肌分化的分泌蛋白[33-35]。综上所述，miR-1和miR-206通过调控许多与增殖密切相关的基因，影响肌肉发育。
2.1.3 miR-1，miR-206靶向在肌肉发育中与细胞融合相关的基因成肌分化过程中，肌细胞发生融合。Fst是促进细胞融合的因子，且是成肌分化抑制因子Mstn的拮抗剂，miR-1靶向Fst[36]。另外，miR-1，miR-206均靶向Gja1和Cx43，它们是胞间隙连接通道，在成肌细胞生长和融合之前和整个过程中高表达，在胚胎发育后期下调[28, 37-38]。二者还靶向Utrn，它是另一个在骨骼肌终末端分化时被抑制的基因[39]。
2.1.4 miR-1和miR-206调控肌肉再生肌肉受到损伤时，原本处于静息状态的卫星细胞活跃起来，重新进入细胞周期[40]。miR-1和miR-206在肌肉损伤时先显著下调，随后逐渐上调，与其在成肌细胞分化过程中的表达一致[25, 34, 41]。且敲除miR-206时，肌肉再生延缓并加剧了mdx小鼠的营养不良表型[34]。由于肌肉再生过程与骨骼肌发育大致相似，因此，许多之前被证明参与成肌分化调控的miRNA也调控肌肉再生。miR-1和miR-206在横纹肌肉瘤中低表达，重新表达miR-206促进了成肌分化，肿瘤生长受到抑制[42]。
2.2 miR-133与成肌分化与miR-1，miR-206相似，miR-133的表达也受Hmox1，YY1和Mtor的调控[18, 21, 36]。在C2C12细胞中过表达miR-133a能显著增强肌管的形成[43]。而敲除miR-133a的小鼠，表现出中央核肌病，线粒体功能障碍，肌纤维形态受损[44]。同时，Liu等[44]发现Dnm2，Pfn2和Calm1都是miR-133a的靶基因，充分表明miR-133a对正常肌肉发育的重要性。miR-133还靶向Ucp2，它的新功能是作为肌肉发育的阻碍者，Myod通过上调miR-133也参与对Ucp2的调控[45]。
miR-133还与细胞命运决定以及肌肉再生相关。Runx2，Trps1，Prdm16分别负责成骨细胞，软骨细胞，脂肪细胞的发育，miR-133同时靶向这些基因[46-47]。因而，miR-133可抑制细胞向其他方向分化，从而有利于向骨骼肌的发育。另一方面，miR-133a和miR-1分别靶向Sp1，Ccnd1，这对细胞周期抑制和合适的肌肉分化是必须的[48]。在肌肉损伤前注射miR-1、miR-206和miR-133，可以增强成肌分化标志蛋白Myog、Myod1和Pax7的表达，促进肌肉再生[49]。
2.3 miR-208, miR-499与成肌分化miR-208a，miR-208b和miR-499是分别在Myh6，Myh7和Myh7b三个肌球蛋白基因内含子表达的miRNA [13, 50]。miR-208a调控两个慢肌球蛋白和它们基因内表达的miRNA，通过结合到Myh7的抑制蛋白，促进Myh7和miR-208b的表达；而且，miR-208a也能调控Myh7b和miR-499的表达；与miR-208a相似，miR-208b抑制Myh7b的抑制蛋白，从而上调它和miR-499的表达[50]。miR-208b和miR-499的成熟序列相似，被报道的靶基因有重叠，功能有互补[50]。他们靶向Sox6，Purb，Sp3，Med13，Cbx1等基因，从而激活慢肌肉发育相关基因的程序，在肌纤维转化成Ⅰ型肌纤维时起关键作用[50-51]。这些基因的下调进一步刺激miR-208b和miR-499的表达。Mapk6和Mstn是肌肉生长的负调控因子，也被证明是miR-499的靶基因[52-53]。
2.4 miR-486与成肌分化miR-486是最新的归为肌肉特异表达的miRNA家族成员，它不具有肌肉特异表达特征，但是在肌肉发育过程中起重要作用。例如，它靶向Pax7，在肌肉分化时明显上调，促进成肌分化[26]。由于它的表达受Myod1、Srf、Mkl1和Sgpl1的调控，它对Pax7的抑制主要是Myod1的上调导致的[26, 54-55]。另外，miR-486直接抑制Pten和Foxo1，还有Pdgfrb，Srsf1，Srsf3，正调控Pik3ca/Akt通路[54, 56]。在成肌细胞中抑制miR-486的表达，则导致细胞不能迁移，融合受阻，相反，过表达miR-486，会导致肌肉再生缺陷[57]。
3 调控成肌分化的非myo-miR除了myo-miR，还有一些在组织内广泛表达的miRNA在肌肉发育中发挥重要功能，例如，miR-27，miR-29，miR-128，miR-199a和miR-431等。
3.1 miR-27与成肌分化miR-27靶向Mstn和Pax3，在肌肉发育中有重要调控作用[58-59]。McFarlane等[59]的研究更加深入，证明miR-27通过负调控Mstn，在激活卫星细胞，成肌细胞增殖和阻止肌肉萎缩起重要作用；该研究还阐明Mstn通过Smad3通路调控miR-27的表达，形成环路，进一步抑制其自身的表达。Pax3表达量的调控极其重要，体内转基因表达miR-27a和肌肉再生的研究以及在卫星细胞中抑制miR-27表达等均表明miR-27调控Pax3，这种下调保证细胞快速健康地进入成肌分化程序[60]。
3.2 miR-29与成肌分化miR-29在出生后的小鼠骨骼肌和成肌分化时表达均上调，是一个促进成肌分化的重要miRNA[61]。miR-29与其靶基因之间形成了重要的调控环路。首先，Nfkb和YY1负调控miR-29b/c的表达，而miR-29靶向YY1，从而形成负反馈通路，使miR-29表达上调从而促进成肌分化；在横纹肌肉瘤中，Nfkb-YY1-29的环路被发现异常调控；因此，miR-29行使着抑癌因子的功能，为肌肉瘤治疗提供思路[62]。在慢性肾病伴随肌肉萎缩的小鼠中，同样发现miR-29靶向YY1并异常表达[63]。另一个调控环路是，TGF-β抑制miR-29的表达，使其靶基因Hdac4上调；而miR-29可以通过靶向Smad3，削弱TGF对它的抑制，从而下调Hdac4，利于成肌分化[64]。YY1/Rybp/Ezh2复合体调控miR-29表达从而影响成肌细胞分化的机制也已阐明，TGF-β-Smad3通路激活时，Myod被降解，miR-29仍然受到抑制，Collagen和Lims1等上调表达，成肌细胞向成纤维细胞分化[65-66]。miR-29还可靶向Akt3，一个负责生长因子信号通路应答的丝氨酸苏氨酸蛋白激酶家族，调控骨骼肌生长并促进其分化[61]。
3.3 miR-128与成肌分化miR-128在脑和骨骼肌中以及成肌分化时高表达，靶向调控胰岛素信号通路中的基因：Insr、Irs1和Pik3r1。TNF-α负调控miR-128，从而正调控胰岛素通路，体内和体外实验表明，抑制miR-128，诱导肌管成熟和肌管肥大[67]。miR-128还可靶向Mstn和Sp1进而抑制成肌细胞增殖，促进分化[68-69]。
3.4 miR-199a与成肌分化miR-199a在肌肉营养不良蛋白缺陷的斑马鱼，mdx小鼠，人肌肉疾病活检中均表达异常，miR-199a的表达受Srf和心肌蛋白相关转录因子调控，它靶向Wnt通路中的Fzd4，Jag1，Wnt2；在斑马鱼中转基因表达miR-199a，导致多种异常现象[70]。miR-199a还可靶向TGF-1/AKT/mTOR通路中的Igf-1，mTOR，Rps6ka6；miR-199的表达在发育，生长，再生以及不同肌肉疾病和肿瘤中等几个关键的时间点都受到调控，过表达miR-199时阻碍成肌分化，抑制时促进分化，肌管肥大[71]。
3.5 miR-431与成肌分化研究发现，miR-431是一个主要在骨骼肌中表达的miRNA，通过靶向Pax7，促进肌肉再生和改善肌肉萎缩症；在mdx小鼠中，miR-431削弱肌肉营养不良的表型，可能是肌肉疾病中潜在的治疗靶点；该研究构建的miR-431转基因小鼠，是一个研究低表达Pax7的卫星细胞生物学功能的基因模型[72]。miR-431还与衰老密切相关，它在衰老的成肌细胞中显著下调，其靶基因Smad4表达上调；在肌肉损伤的小鼠中注射miR-431，Smad4的水平下调并显著提高再生能力；因而，miR-431在维持随着年龄增长的骨骼肌的成肌分化能力上起着重要作用[73]。
4 lncRNA与miRNA相互作用，调控成肌分化最近几年，lncRNA引起了研究者的密切关注。目前，在肌肉发育过程中，有四个lncRNA的功能研究较多。他们分别是linc-MD1，Yam-1，sirt1 AS lncRNA和H19，这些lncRNA都与一个或几个miRNA相互作用，影响成肌分化[74-77]。linc-MD1是一个肌肉特异的lncRNA，在小鼠和人的成肌细胞中作为竞争性RNA，是miR-133和miR-135的海绵体，可通过二者调控Maml1和Mef2c的表达；下调或过表达linc-MD1分别抑制和促进肌肉分化进程，且在人杜氏肌营养不良的肌肉细胞中，linc-MD1表达显著下调[77]。另外，linc-MD1的表达受到HuR蛋白的正向调控，HuR还可协助linc-MD1招募miR-133，而miR-133靶向HuR，因此，三者之间相互作用在早期的成肌分化和进入分化后的调控极其重要[78]。通过Chip实验发现YY1正向调控一个肌肉相关的lncRNA——Yam-1，它是成肌分化的抑制因子，沉默Yam-1可促进损伤诱导的肌肉再生；而Yam-1顺式调节miR-715，它靶向Wnt通路中的Wnt7b；至此，形成YY1-Yam-1-miR-715-Wnt7b之间的调控通路[74]。sirt1 AS lncRNA是一个在脾脏中表达高，肌肉中表达较少的lncRNA，由Sirt1的反义链编码，且可激活Sirt1的表达；C2C12细胞中，上调表达的miR-34a靶向Sirt1，sirt1 AS lncRNA通过与miR-34a竞争结合到sirt1 mRNA 3′UTR形成RNA复合物促进其翻译，从而抑制肌肉发育[76, 79]。H19这一长链非编码RNA在胚胎组织中大量表达，出生后被抑制，仅在骨骼肌中持续表达；H19的一号外显子编码miR-675，它是在成肌分化中诱导表达的miRNA；miR-675直接靶向Smad1，Smad5和Cdc6抑制H19的表达，细胞分化受到抑制，在H19缺陷的小鼠中，通过重新表达miR-675，骨骼肌再生能力得到恢复；因此，H19通过基因内miRNA的表达，在肌肉分化和再生时有重要的反式调控功能[75]。
5 结语综上所述，对肌肉特异表达的miRNA在成肌分化过程中的功能研究非常多且机制已经比较透彻，而近年来更多的非肌肉特异表达的miRNA的功能得到阐明，这充分证明了miRNA对成肌分化调控的重要性。本实验室以C2C12细胞为材料，对小鼠720个miRNAs进行高通量筛选，鉴定了39个新的与成肌分化相关的miRNA，且对miR-17-92家族，miR-195/497，miR-34b以及miR-132的功能进行了研究[80-81]。成肌分化过程中有重要调控作用的miRNA，在各种肌肉疾病中通常有异常表达，因而，对这些miRNA调控机制的研究，最终为肌肉相关疾病的治疗提供思路。
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