妊娠早期叶酸缺乏对仔猪骨骼肌mRNA表达谱的影响及其表观遗传机制研究
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摘要
孕期叶酸缺乏（folate deficiency, FD）能够引起胎儿宫内发育迟缓（intrauterine growthretardation, IUGR），而骨骼肌发育不良是IUGR的主要表征。然而，叶酸缺乏对骨骼肌发育的影响及其分子机制还不明确。近年来，提高肉质水平已成为21世纪养猪业及育种专家新的攻关方向；在人类孕前孕后补充叶酸对后代的长远影响已受到专家的质疑并将成为新的研究热点。本研究探讨叶酸的缺乏及补充对骨骼肌形成及发育的影响，旨在为肉质改善和临床叶酸营养提供有力的实验支持。首先，我们以猪为动物模型，观察孕早期叶酸缺乏对仔猪骨骼肌性状及mRNA表达谱的影响。在我们的研究中，全同胞关系的长白猪与莱芜猪作为杂交体系，在怀孕0-6个月喂养叶酸缺乏饲料或正常饲料，观察初生仔猪背最长肌（Longissimus dorsi, LD）性状并收集标本，用4×44KAgilent猪芯片进行表达谱检测。无论在正交组（LR♂×LW♀）还是反交组（LW♂×LR♀），叶酸缺乏组出生仔猪体重均低于正常对照组，而对仔猪体长体高无显著影响；叶酸缺乏组仔猪肌纤维密度降低，LD中甘油三酯含量更高。芯片结果显示在LR♂×LW♀叶酸缺乏组与对照组比较，子代LD中有3154个基因差异表达，而反交组有3885个差异基因（differentially expressed genes, DEGs）；结果还表明在正反交之间叶酸主要通过影响不同的差异基因而发挥作用。功能分析表明，孕期母猪叶酸缺乏影响了仔猪LD中几乎所有的生物学过程；GO与KEGG筛查出脂肪发育及脂代谢相关的基因与通路，说明母猪叶酸缺乏可能通过调控相关基因而影响了仔猪的脂肪沉积。
另一方面，C2C12细胞株在低血清诱导条件下能够分化为多核的肌管，是体外研究成肌细胞增殖和分化的首选模型。我们以C2C12为模型，分别研究叶酸对成肌细胞增殖及分化的影响并探讨其可能的机制。C2C12培养于乏叶酸培养基D2429中来观察叶酸对肌形成的影响。根据叶酸浓度分成三个组：叶酸缺乏组（Folate-0mg/l，L），正常叶酸浓度组（Folate-4mg/l，N）及高叶酸浓度叶酸组（Folate-40mg/l，H）。我们首先研究叶酸对C2C12增殖及分化的影响，结果发现叶酸缺乏能够促进C2C12细胞增殖而抑制其分化，而高浓度叶酸能促进C2C12的增殖及分化。在C2C12增殖过程中，正常组MyoD mRNA表达明显高于叶酸缺乏与高浓度叶酸组（P<0.05）。通过亚硫酸盐测序（bisulphite sequencing，BS）发现MyoD转录起始位点（Transcription start site，TSS）上游-16bp to+26bp中的5个CpG位点在H组高甲基化，在N组低甲基化。在C2C12分化过程中，我们发现随着叶酸浓度的升高Myogenin mRNA表达增强；在检测的-374bpto+6bp380bp中，靠近TSS的第7和第8CpG位点在高H组高甲基化，而在L组第5和第9位点高甲基化，在L组第2、3、4位点高甲基化；Myogenin第一外显子区甲基化情况在三组之间没有明显不同。叶酸可能正是通过影响基因启动子区CpG位点甲基化情况而影响MyoD和Myogenin的表达。
我们进一步利用MeDIP-chip技术检测了叶酸对C2C12分化过程中全基因组甲基化的影响。结果表明每两组之间启动子区和CpG岛区都存在大量差异甲基化区域（differentially methylated regions, DMRs）。启动子区的DMRs又根据CpG含量分为HCP、ICP及LCP，在各组之间DMRs主要是HCP；各组之间CpG岛中的DMRs主要位于启动子区CpG岛中。在N vs L之间启动子区共有180DMRs （84hypermethylatedand96hypomethylated），在H vs L之间共有199DMRs （95hypermethylated and104hypomethylated），在H vs N之间共有201DMRs （104hypermethylated and97hypomethylated）。在甲基化谱中N vs L与H vs L存在较多的common DMRs；而无论是甲基化上调还是甲基化下调的DMRs比较，N vs L与H vs L之间common DMRs均较少。对DMRs所在基因进行功能分析表明N vs L的DMRs主要富集于细胞分化及发育过程，而H vs L的DMRs更多富集于细胞周期及各种细胞代谢过程。说明从叶酸缺乏状态补充到正常叶酸浓度状态，与从正常叶酸浓度补充到高浓度叶酸状态是通过调控不同基因甲基化状态及不同的生物学过程而影响C2C12的分化。对甲基化谱及表达谱关联分析表明，DMRs与DEGs之间存在一些关联基因，也就是说在C2C12分化过程中，不同浓度叶酸对基因启动子区甲基化的影响可能是一些基因差异表达的直接原因；另一方面，我们可以看出两组之间的DMRs并不是DEGs的唯一原因，即在不同浓度叶酸条件下引起的基因差异表达是各种调控综合作用的结果。
总之，本研究结果显示孕期叶酸缺乏能够改变仔猪背最长肌的基因表达从而影响仔猪骨骼肌的形成，并且母猪叶酸缺乏能够影响仔猪的脂肪沉积。另一方面，体外细胞水平研究发现叶酸缺乏与补充能够影响C2C12的增殖及分化，DNA甲基化是叶酸调控骨骼肌形成的重要机制之一。本研究将为肉质改良及叶酸营养研究提供遗传学和表观遗传学研究基础。
Folate deficiency during pregnancy can cause fetal intrauterine growth restriction, of whichthe skeletal dysplasia is a major manifestation. However, the effect of folate deficiency onskeletal muscle development and its molecular mechanisms are unknown. Factors influencingmuscle development are very important in the formation of porcine meat quality trait. Thisresearch was to discuss the effects of folate deficiency during pregnancy on development ofthe skeletal muscle in piglets, aimed at providing strong experimental support for meat qualityimprovement and clinical folate nutrition. Firstly, we take the pig as the animal model todetermine the effect of maternal folate deficiency on the skeletal muscle transcriptome ofpiglets. In our study full-sibling Landrace (LR) and full-sibling Chinese local breed Laiwu(LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficientor a normal diet during early-mid gestation. Longissimus dorsi (LD) muscle samples werecollected from newborn piglets and a4×44K Agilent porcine oligo microarray was used fortranscriptome analysis of porcine LD muscle. The results showed that folate deficiency duringearly-mid pregnancy affected piglet body weight, LD muscle fiber number and content ofintramuscular triglyceride. The microarray results indicated that3154genes weredifferentially expressed between folate deficient and normal piglets from the LR♂×LW♀cross, and3885differentially expressed genes (DEGs) in the ones from the LW♂×LR♀cross. Most of the genes that are regulated by folate deficiency in the LD muscle of pigletswere different between LR♂×LW♀and LW♂×LR♀crosses. From functional analyses,sow folate deficiency affected almost all biological processes in the progeny. Lipidmetabolism-related genes and associated metabolic pathways were regulated extensively byfolate deficiency, especially in LR♂×LW♀cross piglets.
On the other hand, mouse C2C12myoblast cells are an system widely used to study genesthat regulate muscle growth and differentiation in vitro. In this study, we take C2C12as thecell model to study the effect of folate deficiency and supplement on proliferation anddifferentiation of myoblasts and its possible mechanisms. C2C12cultured in D2429(mediumlack of folic acid) was used to analyze the effect of folic acid on myogenesis. According to thefolic acid concentration, three groups were divided: folate deficiency (Folate-0mg/l, L),normal folate (Folate-4mg/l, N) and high folate supplement (Folate-40mg/l, H).We firstly studied the effect of folate on proliferation and differentiation of C2C12cells, and found thatfolate deficiency can promote proliferation and inhibit the differentiation of C2C12cells,while high folate can promote the proliferation and differentiation of C2C12cells. In theprocess of C2C12proliferation, the mRNA expression of MyoD in normal folate medium wassignificantly higher than that in folate deficiency and high folate medium (P<0.05). Bybisulphite sequencing, we found that five CpG sites located from-16bp to+26bp DNAaround TSS of MyoD were hypermethylated in high folate group, while were hypomethylatedin normal folate. We also found that in the process of C2C12differentiation, the expression ofMyogenin was enhanced along with the increase of folic acid concentration, and that the2nd,3rd and4th CpG loci located from-374bp to+6bp DNA of Myogenin TSS werehypermethylated in normal folate medium, the7th and8th CpG loci were hypermethylated inhigh folate and the5th and9th ones were hypermethylated in folate deficiency group.However, DNA methylation of the first exon of Myogenin was not significantly differentamong three groups.
In addition, we tested the influence of the folic acid on genome-wide methylation changesduring C212differentiation by MeDIP-chip. We found that hundreds of genes werehypermethylated or hypomethylated in each group, and differentially methylated regions(DMRs) were found between every two groups both in promoter and in CpG islands. Forexample,180DMRs (84hypermethylated and96hypomethylated) exist in promoter betweenN and L,199(95hypermethylated and104hypomethylated) in H vs L and201(104hypermethylated and97hypomethylated) in H vs N. In methylation profile, we found onlyfew common DMRs between N vs L and H vs N. It showed that different genes wereregulated in folate deficiency and high folate group to regulate C2C12differentiation.Correlation analysis between methylation profile and expression profile revealed that somegenes were regulated by methylation status directly, but at the same time, DNA methylationwas not the only factor to regulate gene expression.
In conclusion, our results showed that folate deficiency in sows during early-midpregnancy altered the transcriptome of the longissimus dorsi muscle in the offsprings, thusaffecting the process of myogenesis in fetal pigs. We also found that folate deficiency andsupplement can influence the proliferation and differentiation of C2C12, and that DNAmethylation is an important factor regulating genes underlying myogenesis. This studyprovides genetic and epigenetic basis for meat quality improvement and folic acid nutrition.
另一方面，C2C12细胞株在低血清诱导条件下能够分化为多核的肌管，是体外研究成肌细胞增殖和分化的首选模型。我们以C2C12为模型，分别研究叶酸对成肌细胞增殖及分化的影响并探讨其可能的机制。C2C12培养于乏叶酸培养基D2429中来观察叶酸对肌形成的影响。根据叶酸浓度分成三个组：叶酸缺乏组（Folate-0mg/l，L），正常叶酸浓度组（Folate-4mg/l，N）及高叶酸浓度叶酸组（Folate-40mg/l，H）。我们首先研究叶酸对C2C12增殖及分化的影响，结果发现叶酸缺乏能够促进C2C12细胞增殖而抑制其分化，而高浓度叶酸能促进C2C12的增殖及分化。在C2C12增殖过程中，正常组MyoD mRNA表达明显高于叶酸缺乏与高浓度叶酸组（P<0.05）。通过亚硫酸盐测序（bisulphite sequencing，BS）发现MyoD转录起始位点（Transcription start site，TSS）上游-16bp to+26bp中的5个CpG位点在H组高甲基化，在N组低甲基化。在C2C12分化过程中，我们发现随着叶酸浓度的升高Myogenin mRNA表达增强；在检测的-374bpto+6bp380bp中，靠近TSS的第7和第8CpG位点在高H组高甲基化，而在L组第5和第9位点高甲基化，在L组第2、3、4位点高甲基化；Myogenin第一外显子区甲基化情况在三组之间没有明显不同。叶酸可能正是通过影响基因启动子区CpG位点甲基化情况而影响MyoD和Myogenin的表达。
我们进一步利用MeDIP-chip技术检测了叶酸对C2C12分化过程中全基因组甲基化的影响。结果表明每两组之间启动子区和CpG岛区都存在大量差异甲基化区域（differentially methylated regions, DMRs）。启动子区的DMRs又根据CpG含量分为HCP、ICP及LCP，在各组之间DMRs主要是HCP；各组之间CpG岛中的DMRs主要位于启动子区CpG岛中。在N vs L之间启动子区共有180DMRs （84hypermethylatedand96hypomethylated），在H vs L之间共有199DMRs （95hypermethylated and104hypomethylated），在H vs N之间共有201DMRs （104hypermethylated and97hypomethylated）。在甲基化谱中N vs L与H vs L存在较多的common DMRs；而无论是甲基化上调还是甲基化下调的DMRs比较，N vs L与H vs L之间common DMRs均较少。对DMRs所在基因进行功能分析表明N vs L的DMRs主要富集于细胞分化及发育过程，而H vs L的DMRs更多富集于细胞周期及各种细胞代谢过程。说明从叶酸缺乏状态补充到正常叶酸浓度状态，与从正常叶酸浓度补充到高浓度叶酸状态是通过调控不同基因甲基化状态及不同的生物学过程而影响C2C12的分化。对甲基化谱及表达谱关联分析表明，DMRs与DEGs之间存在一些关联基因，也就是说在C2C12分化过程中，不同浓度叶酸对基因启动子区甲基化的影响可能是一些基因差异表达的直接原因；另一方面，我们可以看出两组之间的DMRs并不是DEGs的唯一原因，即在不同浓度叶酸条件下引起的基因差异表达是各种调控综合作用的结果。
总之，本研究结果显示孕期叶酸缺乏能够改变仔猪背最长肌的基因表达从而影响仔猪骨骼肌的形成，并且母猪叶酸缺乏能够影响仔猪的脂肪沉积。另一方面，体外细胞水平研究发现叶酸缺乏与补充能够影响C2C12的增殖及分化，DNA甲基化是叶酸调控骨骼肌形成的重要机制之一。本研究将为肉质改良及叶酸营养研究提供遗传学和表观遗传学研究基础。
Folate deficiency during pregnancy can cause fetal intrauterine growth restriction, of whichthe skeletal dysplasia is a major manifestation. However, the effect of folate deficiency onskeletal muscle development and its molecular mechanisms are unknown. Factors influencingmuscle development are very important in the formation of porcine meat quality trait. Thisresearch was to discuss the effects of folate deficiency during pregnancy on development ofthe skeletal muscle in piglets, aimed at providing strong experimental support for meat qualityimprovement and clinical folate nutrition. Firstly, we take the pig as the animal model todetermine the effect of maternal folate deficiency on the skeletal muscle transcriptome ofpiglets. In our study full-sibling Landrace (LR) and full-sibling Chinese local breed Laiwu(LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficientor a normal diet during early-mid gestation. Longissimus dorsi (LD) muscle samples werecollected from newborn piglets and a4×44K Agilent porcine oligo microarray was used fortranscriptome analysis of porcine LD muscle. The results showed that folate deficiency duringearly-mid pregnancy affected piglet body weight, LD muscle fiber number and content ofintramuscular triglyceride. The microarray results indicated that3154genes weredifferentially expressed between folate deficient and normal piglets from the LR♂×LW♀cross, and3885differentially expressed genes (DEGs) in the ones from the LW♂×LR♀cross. Most of the genes that are regulated by folate deficiency in the LD muscle of pigletswere different between LR♂×LW♀and LW♂×LR♀crosses. From functional analyses,sow folate deficiency affected almost all biological processes in the progeny. Lipidmetabolism-related genes and associated metabolic pathways were regulated extensively byfolate deficiency, especially in LR♂×LW♀cross piglets.
On the other hand, mouse C2C12myoblast cells are an system widely used to study genesthat regulate muscle growth and differentiation in vitro. In this study, we take C2C12as thecell model to study the effect of folate deficiency and supplement on proliferation anddifferentiation of myoblasts and its possible mechanisms. C2C12cultured in D2429(mediumlack of folic acid) was used to analyze the effect of folic acid on myogenesis. According to thefolic acid concentration, three groups were divided: folate deficiency (Folate-0mg/l, L),normal folate (Folate-4mg/l, N) and high folate supplement (Folate-40mg/l, H).We firstly studied the effect of folate on proliferation and differentiation of C2C12cells, and found thatfolate deficiency can promote proliferation and inhibit the differentiation of C2C12cells,while high folate can promote the proliferation and differentiation of C2C12cells. In theprocess of C2C12proliferation, the mRNA expression of MyoD in normal folate medium wassignificantly higher than that in folate deficiency and high folate medium (P<0.05). Bybisulphite sequencing, we found that five CpG sites located from-16bp to+26bp DNAaround TSS of MyoD were hypermethylated in high folate group, while were hypomethylatedin normal folate. We also found that in the process of C2C12differentiation, the expression ofMyogenin was enhanced along with the increase of folic acid concentration, and that the2nd,3rd and4th CpG loci located from-374bp to+6bp DNA of Myogenin TSS werehypermethylated in normal folate medium, the7th and8th CpG loci were hypermethylated inhigh folate and the5th and9th ones were hypermethylated in folate deficiency group.However, DNA methylation of the first exon of Myogenin was not significantly differentamong three groups.
In addition, we tested the influence of the folic acid on genome-wide methylation changesduring C212differentiation by MeDIP-chip. We found that hundreds of genes werehypermethylated or hypomethylated in each group, and differentially methylated regions(DMRs) were found between every two groups both in promoter and in CpG islands. Forexample,180DMRs (84hypermethylated and96hypomethylated) exist in promoter betweenN and L,199(95hypermethylated and104hypomethylated) in H vs L and201(104hypermethylated and97hypomethylated) in H vs N. In methylation profile, we found onlyfew common DMRs between N vs L and H vs N. It showed that different genes wereregulated in folate deficiency and high folate group to regulate C2C12differentiation.Correlation analysis between methylation profile and expression profile revealed that somegenes were regulated by methylation status directly, but at the same time, DNA methylationwas not the only factor to regulate gene expression.
In conclusion, our results showed that folate deficiency in sows during early-midpregnancy altered the transcriptome of the longissimus dorsi muscle in the offsprings, thusaffecting the process of myogenesis in fetal pigs. We also found that folate deficiency andsupplement can influence the proliferation and differentiation of C2C12, and that DNAmethylation is an important factor regulating genes underlying myogenesis. This studyprovides genetic and epigenetic basis for meat quality improvement and folic acid nutrition.
引文
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