猪不同年龄段骨骼肌的差异甲基化组分析
摘要
哺乳动物出生后骨骼肌的生长发育属于典型的数量性状,主要受到微效多基因网络所调控,其中大量关键的功能基因和调控元件的转录又受到DNA甲基化的调控。本研究分别采集了3头180天和7年(平均日龄为2475天)金华猪雌性猪的背最长肌组织样品,利用MeDIP-seq测序技术进行全基因组水平DNA甲基化分析,同时还利用基因芯片技术对样本的mRNA转录组进行测定,进而揭示了两个年龄段背最长肌的甲基化以及转录水平的差异。结果如下：
1、肌纤维表型差异：7年猪骨骼肌肌纤维平均直径显著高于180天(7年：54.89±10.00μmVs.180天：44.85±8.60μm,P<0.01)；7年猪骨骼肌平均肌纤维横截面面积显著高于180天(7年：2544.70±1035.85μm2vs.180天：1680.96±657.44μm2,P<0.01)
2、血清指标差异：7年和180天的猪血清脂蛋白α分别为103.10mg/L和94.10mg/L,两者差异不显著(P>0.05)；180天的胆固醇比7年高31.3%,达到极显著(P=0.004)；180天的低密度脂蛋白比7年的高37.3%,达到显著水平(P=0.03)。表明180天和7年的代谢相关血.清指标存在显著差异。
3、6个样品的MeDIP测序总共产生了46Gb原始序列数据(每个样品约为7.67Gb),通过筛选得到36.6Gb(75.24%)唯一匹配到基因组的非重复序列。
(1)对基因组甲基化水平与染色体相关特征指标进行相关性分析,结果表明甲基化程度与染色体长度成极显著的负相关(r=-0.63,p=0.0036),与GC含量和CpGo/e率成极显著的正相关,相关系数分别为0.787(P<0.01)和0.931(P<0.01)；与每kb的重复数、每Mb的基因数和每Mb的SNP数成正相关,相关系数分别为0.348(P>0.05)、0.516(P<0.05)和0.549(P>0.05)。各染色体的亚端粒区和非亚端粒区之间的甲基化水平存在显著性差异(P<0.05)。(2)24个基因元件之间的甲基化程度存在差异：两个年龄段在高CpG启动子(HCP)和中等CpG启动子(ICP)之间的甲基化程度呈现出极显著差异(P<0.01);两组在ICP和LCP之间的甲基化程度差异达到极显著(P<0.01)。180天在HCP和低CpG启动子(LCP)之间的甲基化程度则达到显著水平(P=0.0275),7年的则不存在显著(P=0.135)。表明ICPs更易被甲基化,这种甲基化状态的改变可能在调控相关基因表达和衰老等生物学过程中发挥着重要的作用。对不同基因组位置的CGI和CGI Shore的甲基化程度进行比较,发现甲基化差异主要体现在基因内和基因间的CGI和CGI Shore中。
4、差异甲基化区域(DMR)分析：180天和7年的DMR有9,234个,占基因组长度的0.064%,所含CpG数目占基因组CpG总数目的28%。
(1)DMR的分布差异：启动子区域内,HCP与LCP相比,DMR在ICP更富集;在D区、I区和P区富集的DMR个数分别是121个(占44%)、82个(占30%)和72个(占26%)；DMR在基因间最为富集,占DMR总数的58.98%;其次为中间的内含子,有2378个,占DMR总数的25.19%。DMR在第一外显子中富集较少；有168个和875个DMR富集在CGI中和CGI Shore中,CGI Shore中DMR数目为CGI中DMR数目的5.21倍。
(2)将启动子区域差异甲基化的基因进行功能富集分析,发现这些差异甲基化的基因富集在蛋白调控的丝裂原激活的蛋白激酶(MAPK)信号通路等52个GO和Pathway中(228个基因,P=0.05),所涉及的生物学功能可能影响肌肉组织的生长发育。从一定程度上揭示了两个年龄段的骨骼肌表型差异的分子基础。
5、转录水平的差异：
(1)芯片数据的可靠性：①芯片的检出率高且集中在61%～69%之间；②芯片的重复性探针变异系数(C.V)在3.5%-6.5%之间,均高于C.V<15%的成功实验标准；③箱图(Box plot)的结果也显示芯片数据具有很相似的离散度,说明标准化的效果比较理想。这些结果均表明本研究结果准确可靠,检测数据能够真实反映基因的表达变化规律。
(2)本研究芯片共43,663个探针(以60mer的长度),检出23,283个探针(占53.32%)表达超过阈值,比对到猪参考基因组(猪10.2版本)对应22,043个基因,有4,184个基因表达量在两组间差异显著(P<0.05),其中,7年相对180天的上调基因和下调基因分别有2,012个和2,172个。
(3)对差异基因进行功能富集分析,得到199个显著的GO和Pathway(3212个基因,P=0.05),如转化生长因子(TGF)调控的TGF-β受体结合通路、热应激因子(HSF)诱导的热应激蛋白结合通路和整合素、蛋白聚糖、CD36介导的细胞外基质(ECM)受体通路等,揭示了肌肉组织的生长发育及其增龄性的变化可能与这些过程和通路相关。
6、甲基化介导的基因表达差异：在3,212个差异表达基因中,有46个启动子区域存在甲基化差异,其中16个基因的启动子甲基化程度与其基因表达量呈正相关(r=0.759,P=0.0007),如MYO5C、ALDOC和MYL12B等；其它30个基因的启动子甲基化程度与其基因表达量呈负相关(r=-0.647,P=0.0001),如GPR143、GRN和NTF32等。揭示本研究中发现的差异基因可能参与了肌肉的生长发育及其增龄性变化。比如,KCNB1基因、MyoZl基因和SEPN1基因等。
7、为了验证试验的准确性,本试验还利用BSP技术验证了ALDOC和KCNB1基因的甲基化程度,发现两种技术的结果一致。对启动子区域的差异甲基化基因以及差异表达mRNA分别进行功能富集分析,发现甲基化和mRNA差异的基因均富集在生物学粘附、循环系统进程、血液循环、细胞增殖的调控和对内源性刺激的反应、铁离子结合和ATP酶活性6个生物学过程,表明这些过程对生物体的发育具有重要的作用。
本研究筛选出了对于猪骨骼肌的生长发育可能具有重要影响和较大研究价值的功能基因,初步揭示了在肌肉生长发育及其增龄性变化中的基因表达调控及局部分子互作机制,以及造成猪肌肉宏观性状表型差异的表观调控模式。
The growth and development of skeletal muscle postnatal belongs to the typical quantitative character, and it is regulated by the regulation net that mainly consists of related minorgene. The DNA methylation plays a key role in regulation of these functional genes and the transcription of regulatory element.
A total of six healthy Jinhua pigs of two age groups were used in this study.3pigs in180days old and3pigs in seven years old (the average age in2,475days). The longissimus dorsi muscles were sampled rapidly from each carcass and were analyzed for the DNA methylation by using the MeDlP-Seq approach. Moreover, we also investigated the differences of mRNA transcriptomes between these two age stages. This study preliminarily revealed the methylation and transcriptional differences of the Longissimus dorsi in two age stages.
I The average diameter of the Longissimus dorsi muscle were significantly (P<0.01) different between the180days and7years groups, the values were (44.85±8.60) μm and (54.89±10.00) μm, respectively; and cross sectional area of180days-aged and7years-aged also were significantly(P<0.01), the values were (1680.96+657.44) μm2and (2544.70+1035.85) μm2, respectively.
II The lipoprotein α content of180days aged pigs (103.10mg/L) were higher than that of the7years-aged pigs (94.10mg/L)(P>0.05); the cholesterol of180days aged pigs was31.3%higher than that of7years-aged pigs (P=0.004); the low density lipoprotein of180days aged pigs was37.3%higher than that of the years aged pigs (P=0.03).
III A total of46Gb methylated DNA immunoprecipitation sequencing (MeDIP-seq) data were generated from six samples (about7.64Gb data for each sample), of which75%unique reads (-36.56Gb) were uniquely mapped to the pig genome.
(i) We found that methylation level across the choromosome negatively correlated with chromosomal length (Pearson's r=0.633, P=0.0036) and positively correlated with GC content (Pearson's r=0.787, P=6.49×10-5), SNP density (Pearson's r=0.549, P=0.0149), gene density (Pearson's r=0.516, P=0.0236),density of repeat region (Pearson'r=0.0348, P=0.145). and especially with CpGo/e ratio (Pearson's r=0.931, P=7.41×10-9).We also found the different methylation level presented in the subtelomeric region of each chromasome.
(ii) ICP in both young and middle-aged pigs exhibited relativley higher methylation level than HCP and LCP (P<0.01). The majority of methylated CpG Island located in intragenic and intergenic regions, whereas the CpG Island in promoter showed hypomethylated. It demonstrated that ICPs were more susceptible to methylation and this kind of alteration of methylation status in ICP may play important role in modulating relevant gene expression and involved in some biological process such as aging.
IV In total9,234DMR were identified which accounted for6.41%of genomic length and28%of genomic CpG number..
(i) For promoters, more DMRs were enriched in ICPs when compared with HCPs and LCPs. Distal(D), intermediate (Ⅰ) and proximal (P) regions of promoters contained121(occupied44%),82(occupied30%) and72(occupied26%), respectively. This result reveals the D regions of promoters contained14%more of DMRs than I regions, and18%more of DMRs than P regions. The vast majority of DMRs (5,567DMRs which occupied58.98%of gene bodies) located in intergenic followed by the medial intron (2,378DMRs, occupied25.19%of gene bodies). The first exon contained relatively low DMRs within the gene body. DMRs enriched in CGI (168) and CGI Shore (875).Then, in CGI Shore, there were287(occupied27.52%of all CGI Shore),224(occupied21.47%of all CGI Shore) and270(occupied25.98%of all CGI Shore)
(ii) In order to know the change of expression, functional enrichment analysis of differential methylated genes (228genes, P<0.05)was employed. The results revealed a total of52GO and pathways including the pathway of mitogen-activated protein kinase (MAPK), which may have an effect on skeletal muscle development. Based on the results, we can speculate the molecular basis of muscle phenotypic variation between the180days-aged and the7years-aged pigs.
V(i) Reliability of chip data:It is revealed that the chip data is reliable and accurate. Repeatability analysis indicated that average coefficient of variation (C. V) within arrays were between3.5%～6.5%for expression profilingof longissimus dorsi muscle. The Box Plot also showed the similar dispersion. These resultes demonstrate that the microarray technique used in this study is accurate and reproducible.
(ii) A total of43,663probes (size in60mer) were generated from six samples, of which23,283unique probes were aligned to the pig genome and were mapped to22043genes. There were total4,184differently expressed genes (P<0.05), of which2,012were up-regulated and2,172were down-regulated in the comparision of7yeras vs.180days. And among them3,212(7.36%) genes was unigene.
(iii) The top ten Go and pathways like as heat shock fator, transforming growth factor and extracellular matrix,which may regulate growth and development of muscle between180days-aged and7years-aged pigs.
VI Of the888differently expressed genes, pomoter region of46genes showed different methylation level, of which16genes showed positively correlation (r=0.759, P=0.0007) between the promoter methylation and mRNA expression level, eg. MYO5C、ALDOC and MYL12B et al.; and30genes showed negtively correlation (r=-0.647, P=0.0001), eg. GPR143、 GRN and NTF32et al. The genes of ALDOC and KCNB1result by BSP also verfied the same trends in the DMR.
VII The same GO or pathway was mapped of the difference genes in DMRs and mRNA revealed that there have5GO or pathway, including the circulatory system process, iron ion binding and ATPase activity,etc.
These results highlight some possible candidate functional genes that have great influence and more research value for the growth and development of skeletal muscle of porcine, and preliminary revealed the partial molecular interaction mechanism of the gene exprssion and regulation during the growth and development of skeletal muscle with aging, and also reaveld the epigenetic regulation pattern in the formation of macroscopical phenotypic difference in porcine skeletal muscle.
1、肌纤维表型差异：7年猪骨骼肌肌纤维平均直径显著高于180天(7年：54.89±10.00μmVs.180天：44.85±8.60μm,P<0.01)；7年猪骨骼肌平均肌纤维横截面面积显著高于180天(7年：2544.70±1035.85μm2vs.180天：1680.96±657.44μm2,P<0.01)
2、血清指标差异：7年和180天的猪血清脂蛋白α分别为103.10mg/L和94.10mg/L,两者差异不显著(P>0.05)；180天的胆固醇比7年高31.3%,达到极显著(P=0.004)；180天的低密度脂蛋白比7年的高37.3%,达到显著水平(P=0.03)。表明180天和7年的代谢相关血.清指标存在显著差异。
3、6个样品的MeDIP测序总共产生了46Gb原始序列数据(每个样品约为7.67Gb),通过筛选得到36.6Gb(75.24%)唯一匹配到基因组的非重复序列。
(1)对基因组甲基化水平与染色体相关特征指标进行相关性分析,结果表明甲基化程度与染色体长度成极显著的负相关(r=-0.63,p=0.0036),与GC含量和CpGo/e率成极显著的正相关,相关系数分别为0.787(P<0.01)和0.931(P<0.01)；与每kb的重复数、每Mb的基因数和每Mb的SNP数成正相关,相关系数分别为0.348(P>0.05)、0.516(P<0.05)和0.549(P>0.05)。各染色体的亚端粒区和非亚端粒区之间的甲基化水平存在显著性差异(P<0.05)。(2)24个基因元件之间的甲基化程度存在差异：两个年龄段在高CpG启动子(HCP)和中等CpG启动子(ICP)之间的甲基化程度呈现出极显著差异(P<0.01);两组在ICP和LCP之间的甲基化程度差异达到极显著(P<0.01)。180天在HCP和低CpG启动子(LCP)之间的甲基化程度则达到显著水平(P=0.0275),7年的则不存在显著(P=0.135)。表明ICPs更易被甲基化,这种甲基化状态的改变可能在调控相关基因表达和衰老等生物学过程中发挥着重要的作用。对不同基因组位置的CGI和CGI Shore的甲基化程度进行比较,发现甲基化差异主要体现在基因内和基因间的CGI和CGI Shore中。
4、差异甲基化区域(DMR)分析：180天和7年的DMR有9,234个,占基因组长度的0.064%,所含CpG数目占基因组CpG总数目的28%。
(1)DMR的分布差异：启动子区域内,HCP与LCP相比,DMR在ICP更富集;在D区、I区和P区富集的DMR个数分别是121个(占44%)、82个(占30%)和72个(占26%)；DMR在基因间最为富集,占DMR总数的58.98%;其次为中间的内含子,有2378个,占DMR总数的25.19%。DMR在第一外显子中富集较少；有168个和875个DMR富集在CGI中和CGI Shore中,CGI Shore中DMR数目为CGI中DMR数目的5.21倍。
(2)将启动子区域差异甲基化的基因进行功能富集分析,发现这些差异甲基化的基因富集在蛋白调控的丝裂原激活的蛋白激酶(MAPK)信号通路等52个GO和Pathway中(228个基因,P=0.05),所涉及的生物学功能可能影响肌肉组织的生长发育。从一定程度上揭示了两个年龄段的骨骼肌表型差异的分子基础。
5、转录水平的差异：
(1)芯片数据的可靠性：①芯片的检出率高且集中在61%～69%之间；②芯片的重复性探针变异系数(C.V)在3.5%-6.5%之间,均高于C.V<15%的成功实验标准；③箱图(Box plot)的结果也显示芯片数据具有很相似的离散度,说明标准化的效果比较理想。这些结果均表明本研究结果准确可靠,检测数据能够真实反映基因的表达变化规律。
(2)本研究芯片共43,663个探针(以60mer的长度),检出23,283个探针(占53.32%)表达超过阈值,比对到猪参考基因组(猪10.2版本)对应22,043个基因,有4,184个基因表达量在两组间差异显著(P<0.05),其中,7年相对180天的上调基因和下调基因分别有2,012个和2,172个。
(3)对差异基因进行功能富集分析,得到199个显著的GO和Pathway(3212个基因,P=0.05),如转化生长因子(TGF)调控的TGF-β受体结合通路、热应激因子(HSF)诱导的热应激蛋白结合通路和整合素、蛋白聚糖、CD36介导的细胞外基质(ECM)受体通路等,揭示了肌肉组织的生长发育及其增龄性的变化可能与这些过程和通路相关。
6、甲基化介导的基因表达差异：在3,212个差异表达基因中,有46个启动子区域存在甲基化差异,其中16个基因的启动子甲基化程度与其基因表达量呈正相关(r=0.759,P=0.0007),如MYO5C、ALDOC和MYL12B等；其它30个基因的启动子甲基化程度与其基因表达量呈负相关(r=-0.647,P=0.0001),如GPR143、GRN和NTF32等。揭示本研究中发现的差异基因可能参与了肌肉的生长发育及其增龄性变化。比如,KCNB1基因、MyoZl基因和SEPN1基因等。
7、为了验证试验的准确性,本试验还利用BSP技术验证了ALDOC和KCNB1基因的甲基化程度,发现两种技术的结果一致。对启动子区域的差异甲基化基因以及差异表达mRNA分别进行功能富集分析,发现甲基化和mRNA差异的基因均富集在生物学粘附、循环系统进程、血液循环、细胞增殖的调控和对内源性刺激的反应、铁离子结合和ATP酶活性6个生物学过程,表明这些过程对生物体的发育具有重要的作用。
本研究筛选出了对于猪骨骼肌的生长发育可能具有重要影响和较大研究价值的功能基因,初步揭示了在肌肉生长发育及其增龄性变化中的基因表达调控及局部分子互作机制,以及造成猪肌肉宏观性状表型差异的表观调控模式。
The growth and development of skeletal muscle postnatal belongs to the typical quantitative character, and it is regulated by the regulation net that mainly consists of related minorgene. The DNA methylation plays a key role in regulation of these functional genes and the transcription of regulatory element.
A total of six healthy Jinhua pigs of two age groups were used in this study.3pigs in180days old and3pigs in seven years old (the average age in2,475days). The longissimus dorsi muscles were sampled rapidly from each carcass and were analyzed for the DNA methylation by using the MeDlP-Seq approach. Moreover, we also investigated the differences of mRNA transcriptomes between these two age stages. This study preliminarily revealed the methylation and transcriptional differences of the Longissimus dorsi in two age stages.
I The average diameter of the Longissimus dorsi muscle were significantly (P<0.01) different between the180days and7years groups, the values were (44.85±8.60) μm and (54.89±10.00) μm, respectively; and cross sectional area of180days-aged and7years-aged also were significantly(P<0.01), the values were (1680.96+657.44) μm2and (2544.70+1035.85) μm2, respectively.
II The lipoprotein α content of180days aged pigs (103.10mg/L) were higher than that of the7years-aged pigs (94.10mg/L)(P>0.05); the cholesterol of180days aged pigs was31.3%higher than that of7years-aged pigs (P=0.004); the low density lipoprotein of180days aged pigs was37.3%higher than that of the years aged pigs (P=0.03).
III A total of46Gb methylated DNA immunoprecipitation sequencing (MeDIP-seq) data were generated from six samples (about7.64Gb data for each sample), of which75%unique reads (-36.56Gb) were uniquely mapped to the pig genome.
(i) We found that methylation level across the choromosome negatively correlated with chromosomal length (Pearson's r=0.633, P=0.0036) and positively correlated with GC content (Pearson's r=0.787, P=6.49×10-5), SNP density (Pearson's r=0.549, P=0.0149), gene density (Pearson's r=0.516, P=0.0236),density of repeat region (Pearson'r=0.0348, P=0.145). and especially with CpGo/e ratio (Pearson's r=0.931, P=7.41×10-9).We also found the different methylation level presented in the subtelomeric region of each chromasome.
(ii) ICP in both young and middle-aged pigs exhibited relativley higher methylation level than HCP and LCP (P<0.01). The majority of methylated CpG Island located in intragenic and intergenic regions, whereas the CpG Island in promoter showed hypomethylated. It demonstrated that ICPs were more susceptible to methylation and this kind of alteration of methylation status in ICP may play important role in modulating relevant gene expression and involved in some biological process such as aging.
IV In total9,234DMR were identified which accounted for6.41%of genomic length and28%of genomic CpG number..
(i) For promoters, more DMRs were enriched in ICPs when compared with HCPs and LCPs. Distal(D), intermediate (Ⅰ) and proximal (P) regions of promoters contained121(occupied44%),82(occupied30%) and72(occupied26%), respectively. This result reveals the D regions of promoters contained14%more of DMRs than I regions, and18%more of DMRs than P regions. The vast majority of DMRs (5,567DMRs which occupied58.98%of gene bodies) located in intergenic followed by the medial intron (2,378DMRs, occupied25.19%of gene bodies). The first exon contained relatively low DMRs within the gene body. DMRs enriched in CGI (168) and CGI Shore (875).Then, in CGI Shore, there were287(occupied27.52%of all CGI Shore),224(occupied21.47%of all CGI Shore) and270(occupied25.98%of all CGI Shore)
(ii) In order to know the change of expression, functional enrichment analysis of differential methylated genes (228genes, P<0.05)was employed. The results revealed a total of52GO and pathways including the pathway of mitogen-activated protein kinase (MAPK), which may have an effect on skeletal muscle development. Based on the results, we can speculate the molecular basis of muscle phenotypic variation between the180days-aged and the7years-aged pigs.
V(i) Reliability of chip data:It is revealed that the chip data is reliable and accurate. Repeatability analysis indicated that average coefficient of variation (C. V) within arrays were between3.5%～6.5%for expression profilingof longissimus dorsi muscle. The Box Plot also showed the similar dispersion. These resultes demonstrate that the microarray technique used in this study is accurate and reproducible.
(ii) A total of43,663probes (size in60mer) were generated from six samples, of which23,283unique probes were aligned to the pig genome and were mapped to22043genes. There were total4,184differently expressed genes (P<0.05), of which2,012were up-regulated and2,172were down-regulated in the comparision of7yeras vs.180days. And among them3,212(7.36%) genes was unigene.
(iii) The top ten Go and pathways like as heat shock fator, transforming growth factor and extracellular matrix,which may regulate growth and development of muscle between180days-aged and7years-aged pigs.
VI Of the888differently expressed genes, pomoter region of46genes showed different methylation level, of which16genes showed positively correlation (r=0.759, P=0.0007) between the promoter methylation and mRNA expression level, eg. MYO5C、ALDOC and MYL12B et al.; and30genes showed negtively correlation (r=-0.647, P=0.0001), eg. GPR143、 GRN and NTF32et al. The genes of ALDOC and KCNB1result by BSP also verfied the same trends in the DMR.
VII The same GO or pathway was mapped of the difference genes in DMRs and mRNA revealed that there have5GO or pathway, including the circulatory system process, iron ion binding and ATPase activity,etc.
These results highlight some possible candidate functional genes that have great influence and more research value for the growth and development of skeletal muscle of porcine, and preliminary revealed the partial molecular interaction mechanism of the gene exprssion and regulation during the growth and development of skeletal muscle with aging, and also reaveld the epigenetic regulation pattern in the formation of macroscopical phenotypic difference in porcine skeletal muscle.
引文
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