母亲高雄激素对子代糖代谢的影响及其表观遗传机制研究
发布时间：2018-07-29 16:11
【摘要】：第一部分母亲妊娠前高雄出生子代随访、印迹基因表达及甲基化状况目的:观察母亲妊娠前高雄出生子代的生长发育及幼年期血压、血脂、血糖情况,研究子代糖代谢相关印记基因表达差异及甲基化改变,评估母亲高雄对子代表型及表观遗传的影响。材料和方法:对2002-2008年在浙江大学医学院附属妇产科医院诊断为高雄激素血症并妊娠成功的患者进行随访,其子代作为实验组,根据其妊娠方式(自然妊娠,促排卵后妊娠,IVF-ET后妊娠)进行匹配,以同期正常自然妊娠或因男性/管性因素经促排卵或IVF-ET后出生子代为对照组,比较分析两组子代围产期情况,生长发育指标,血糖(空腹,口服糖耐量试验OGTT)、血脂及血压水平。利用荧光定量PCR检测子代外周血糖代谢相关父/母源性印记基因表达,利用亚硫氢酸盐测序的方法检测差异表达基因差异甲基化区域(DMR)的甲基化水平。同时收集临床废弃人卵母细胞,体外高雄激素处理后采用免疫荧光检测卵母细胞母源性印迹基因IGF2表达改变。结果:1.本研究共随访80名母亲高雄出生子代及146名对照组子代,高雄子代出生体重、孕周、早产率较对照组均无显著性差异;2.随访时两组子代的年龄、体重指数(BMI)、血压及血脂水平均无显著性差异,母亲高雄出生子代的空腹血糖(4.72±0.04mmol/L vs.4.60±0.03mmol/L,p0.05)、空腹胰岛素(3.58±0.18μU/ml vs.3.12±0.15μU/ml,p0.05)及 HOMA 胰岛素抵抗指数(0.76±0.04 vs.0.66±0.03,p0.05)均显著高于对照组;3.其中74名高雄组子代及66 名对照组进行了 OGTT,两小时血糖(5.12±0.13mmol/Lvs.4.85±0.15mmol/L,p0.05)及胰岛素水平(10.53±2.03μU/mlvs.4.72±1.08μU/ml,p0.01)高雄子代均显著高于对照子代;4.高雄子代外周血淋巴细胞母源性印记基因IGF2及GRB10的表达显著增高,其相应差异甲基化区显著低甲基化;体外雄激素处理后,卵母细胞IGF2表达显著升高。结论:母亲妊娠前高雄出生子代幼年期空腹及糖耐量试验中糖/胰岛素水平均发生改变,但随访中未发现血糖/胰岛素异常的子代;糖代谢相关印记基因IGF2及GRB20表达增高可能与高雄子代糖代谢水平改变有关,甲基化水平降低为印记基因表达上调的机制,提示母亲高雄影响子代表观遗传。第二部分妊娠前高雄大鼠子代表型、亲代卵母细胞及子代胰岛Igf2表达及甲基化检测目的:研究妊娠前高雄大鼠子代的糖/胰岛素代谢状况,评估高雄致子代糖尿病的风险;研究高雄对亲代卵母细胞及子代胰岛中印迹基因Igf2表达及甲基化水平的影响,明确表观遗传改变的传代效应。材料与方法:建立雌性高雄激素大鼠模型,交配前(6周龄)检测血睾酮及游离雄激素指数。7周龄将高雄雌鼠与正常雄鼠交配得到高雄组子代,同龄正常雌鼠与正常雄鼠交配得到对照组子代。检测两组子代的出生体重、幼年期(3周龄)及成年期(8周龄)体重、日能量消耗及饮水量,血糖仪检测空腹血糖并行糖耐量试验,ELISA试剂盒检测胰岛素水平。分离纯化大鼠子代胰岛细胞和亲代MII期卵母细胞,实时定量PCR检测印记基因表达,亚硫酸氢盐测检测IGF2差异甲基化区甲基化状态。结果:1.母亲妊娠前高雄出生子代的出生体重于对照组相比无显著性差异;2.高雄子代自幼年期出现日饮水量增多及日能量消耗增多,且这一表型一直持续至成年期;3.高雄子代空腹血糖显著高于对照组,并且有27%在幼年期即出现糖尿病(GTT30min血糖11.1mmol/L)。发育至成年期,虽然高雄子代的空腹血糖与对照组相比无显著性差异,但在GTT30min及60min时,其血糖水平仍显著高于对照组,且76%的成年高雄子代仍表现出糖尿病;4.高雄子代幼年期空腹及注射葡萄糖后的胰岛素水平均显著低于对照组,成年期空腹胰岛素与对照组无显著性差异,然而注射葡萄糖后其胰岛素水平仍显著低于对照子代;5.高雄子代胰岛细胞Igf2较对照组显著高表达,且胎鼠胰岛中Igf2DMR2甲基化水平显著降低;6.高雄亲代卵母细胞Igf2同样高表达,Igf2DMR2甲基化水平也显著低于对照组,更有趣的是,亲代卵母细胞中3个低甲基化的CpG位点与子代胎胰岛细胞的3个低甲基化CpG位点相对应。结论:1.大鼠母亲妊娠前高雄致子代糖尿病;2.妊娠前高雄出生子代胰岛素释放功能受损,是导致子代糖尿病的主要原因;3.高雄子代胰岛印记基因Igf2表达异常,可能是其胰岛细胞功能不良的机制之一;4.高雄子代胰岛Igf2DMR2甲基化水平降低,为Igf2表达升高的机制;5.妊娠前高雄暴露致卵母细胞Igf2表达及甲基化水平改变,这种异常的表观遗传修饰可从亲代卵母细胞(配子)传递至子代胰岛细胞(体细胞),是母亲高雄致子代糖代谢异常的主要机制之一。第三部分高雄激素对甲基转移酶3a表达的调控目的:研究雄激素对甲基转移酶3a(DNMT3a)表达的调控,从体内及体外细胞培养两个方面探讨雄激素调节DNMT3a表达的分子机制。材料与方法:获取高雄激素造模的大鼠MII卵母细胞,采用免疫荧光比较高雄状态下的卵母细胞与正常卵母细胞DNMT3a表达的差异;体外实验以人原代颗粒细胞及人KGN颗粒细胞为研究对象,通过不同浓度的双氢睾酮(DHT)处理,以及雄激素受体(AR)小干扰RNA处理细胞后再加入不同浓度DHT处理,采用实时定量PCR及Western技术分别检测颗粒细胞中DNMT3a mRNA和蛋白水平的表达改变;在KGN颗粒细胞系中应用实时定量PCR及Western检测不同浓度DHT对转录因子STAT3的调节,并利用染色质免疫共沉淀技术,明确DNMT3a DNA上是否存在STAT3反应元件,进一步确定其结合位点。结果:1.在体实验显示,高雄大鼠卵母细胞中DNMT3a与对照组相比显著低表达;2.体外细胞实验显示,DHT可浓度依赖性的下调原代颗粒细胞DNMT3a mRNA,同时上调印记基因IGF2 mRNA;相应地,DHT可在mRNA水平浓度依赖性的下调KGN细胞DNMT3a的表达;SiRNA敲减AR可阻断DHT对DNMT3a的下调作用;3.DHT可浓度依赖性降低STAT3的表达;4.DNMT3a转录起始位点上游-1118bp处存在着STAT3的结合位点。结论:1.体内高雄可降低大鼠卵母细胞甲基化建立关键酶DNMT3a的表达,这可能是高雄激素干扰卵母细胞母源性印记的建立过程,从而导致其印记基因IGF2甲基化水平降低、表达上调的重要机制;2.人颗粒细胞体外实验显示高雄激素从mRNA及蛋白水平下调DNMT3a的表达,且这一调控是通过雄激素受体通路来进行的;3.DNMT3a启动子区存在转录因子STAT3的反应元件,高浓度雄激素下调STAT3蛋白可能是其从mRNA 转录水平降低DNMT3a表达的机制之一。
[Abstract]:The first part of the mother's pregnancy, Kaohsiung birth subgeneration follow-up, imprinted gene expression and methylation status: Observation of the growth and development of the offspring of Kaohsiung before pregnancy, blood pressure, blood lipid, blood glucose, the difference of the expression of glycometabolism related gene expression and the change of methylation, and the evaluation of the representative and table of the mother of the mother Kaohsiung. Effects of epigenetic effects. Materials and methods: a follow-up of 2002-2008 years at the hospital of Obstetrics and Gynecology, affiliated to the Medical College of Zhejiang University, which was diagnosed as Kaohsiung hormone and pregnancy success, was followed up as an experimental group and matched according to the way of pregnancy (natural pregnancy, ovulatory pregnancy, IVF-ET pregnancy), in the same period of normal natural pregnancy or The perinatal period, growth and development index, blood glucose (fasting, oral glucose tolerance test OGTT), blood lipid and blood pressure level were compared and analyzed in two groups of subgeneration perinatal period, and blood glucose and blood pressure levels were compared between the two groups. The methylation level of differentially expressed genes in the methylation region (DMR) was detected by the acid salt sequencing method. At the same time, the clinical abandoned human oocytes were collected and the oocyte maternal maternal imprinted gene IGF2 expression was detected by immunofluorescence in Kaohsiung. The results were as follows: 1. studies were followed up by 80 mothers in Kaohsiung and 146 pairs. There was no significant difference in birth weight, pregnancy week and preterm birth rate in Kaohsiung subgeneration, and there was no significant difference in the age of the two groups, body mass index (BMI), blood pressure and blood lipid levels in the two groups, and the fasting insulin (4.72 + 0.04mmol/L vs.4.60 + 0.03mmol/L, P0.05) and fasting insulin (3.58 + 0.18 u U/ml) at the birth of the mother. Vs.3.12 + 0.15 U/ml, P0.05) and HOMA insulin resistance index (0.76 + 0.04 vs.0.66 + 0.03, P0.05) were significantly higher than those of the control group. 3. of the 74 Kaohsiung group and 66 control groups had OGTT, two hours blood glucose (5.12 + 0.13mmol/Lvs.4.85 + 0.15mmol/L, P0.05) and Isle level (10.53 + 2.03 mu U/mlvs.4.72 + 1.08 U/ml,) The male progeny was significantly higher than that of the control subgeneration; the expression of IGF2 and GRB10 in the peripheral blood lymphocyte imprinting genes of 4. Kaohsiung progeny increased significantly, and the corresponding differential methylation area was significantly lower methylation. After androgens treated in vitro, the expression of IGF2 in oocytes increased significantly. Conclusion: the fasting and glucose tolerance of the offspring of the parent of the parent of Kaohsiung before pregnancy. The glucose / insulin levels were all changed in the dose test, but the blood glucose / insulin abnormal progeny was not found in the follow-up. The increased expression of IGF2 and GRB20 may be related to the change of sugar metabolism in Kaohsiung substitutes. The reduction of methylation level is the mechanism of the up-regulation of the imprinted gene expression, which suggests that mother Kaohsiung influence the representation of the offspring. Second part of the representative type of Kaohsiung rats before pregnancy, the expression of Igf2 expression and methylation of the oocytes and offspring islets of the parents: To study the glucose / insulin metabolism in the rat of Kaohsiung before pregnancy, to evaluate the risk of diabetes in Kaohsiung, and to study the expression of Igf2 in the parent and offspring islets of the parent and the offspring of the offspring. The effect of epigenetic changes on the generation effect of epigenetic changes. Materials and methods: the female Kaohsiung hormone rat model was established. The blood testosterone and the free androgen index.7 weeks before mating (6 weeks old) were used to mate Kaohsiung female rats with the normal male rats, and the normal female rats of the same age were matched with the normal male rats to get the control group. The birth weight of two groups of offspring, young (3 weeks old) and adult (8 weeks old) body weight, daily energy consumption and drinking water were measured. Glucose meter detected fasting blood glucose and glucose tolerance test, ELISA kit detected insulin level. Isolated and purified rat subgeneration islet cells and parent MII oocytes, real-time quantitative PCR detection of imprinted gene expression, The methylation status of IGF2 differential methylation area was measured by hydrogen sulphite. Results: 1. the birth weight of Kaohsiung birth progeny before pregnancy was not significantly different from that of the control group; 2. Kaohsiung progeny had increased daily drinking water and increased daily energy consumption, and the phenotypes lasted to adulthood; 3. of the Kaohsiung offspring had fasting blood glucose. Significantly higher than the control group, and 27% of the onset of diabetes (GTT30min blood glucose 11.1mmol/L). Development to adulthood, although the fasting blood glucose of the Kaohsiung offspring had no significant difference compared with the control group, but at GTT30min and 60min, the blood glucose level was still significantly higher than that of the control group, and 76% of the adult progeny still showed diabetes; 4. The level of insulin after the infancy and the injection of glucose in the juvenile of Kaohsiung was significantly lower than that in the control group. There was no significant difference between the adult fasting insulin and the control group. However, the insulin level was still significantly lower than that of the control group after the injection of glucose; 5. the Igf2 of the Kaohsiung subgeneration islet cells was significantly higher than that of the control group, and the Igf2DMR in the pancreatic islets of fetal rats was significantly higher than that of the control group. The level of 2 methylation decreased significantly; 6. the Igf2 oocyte in Kaohsiung was also highly expressed, and the level of Igf2DMR2 methylation was also significantly lower than that of the control group. More interestingly, the 3 CpG loci in the parent oocyte were corresponding to the 3 hypomethylation CpG loci of the fetal islet cells. 2. the impaired insulin release in Kaohsiung before pregnancy was the main cause of subgeneration insulin release, which was the main cause of subgeneration diabetes; 3. the expression of islet imprinting gene Igf2 in the 3. progeny of Kaohsiung was one of the mechanisms of its islet cell dysfunction; 4. of the Kaohsiung subgeneration islet islet methylation water decreased, the mechanism of Igf2 expression increased, and 5. before pregnancy. The expression of Igf2 and the change of methylation level in male oocytes. This abnormal epigenetic modification can be transferred from parent oocytes (gametes) to progeny islet cells (somatic cells). It is one of the main mechanisms of abnormal glycometabolism in the offspring of mother Kaohsiung. The third part of the regulation of the expression of methyltransferase 3A by the hormone of the hormone of Kaohsiung: the study of male The regulation of hormone on the expression of methyltransferase 3A (DNMT3a) and the molecular mechanism of androgen regulation of DNMT3a expression from two aspects in vivo and in vitro culture. Materials and methods: to obtain MII oocytes from Kaohsiung hormone model rats, and to compare the difference between the expression of DNMT3a in oocyte and normal oocyte in Kaohsiung state by immunofluorescence In vitro, in vitro, human primary granulosa cells and human KGN granulosa cells were treated with different concentrations of dihydrotestosterone (DHT), and androgen receptor (AR) small interference RNA treated cells and then added to different concentrations of DHT treatment. Real-time quantitative PCR and Western techniques were used to detect DNMT3a mRNA and protein levels in granular cells respectively. Expression changes; in the KGN granular cell line, real-time quantitative PCR and Western were used to detect the regulation of DHT on the transcription factor STAT3, and chromatin immunoprecipitation technique was used to determine whether there was a STAT3 reaction element on DNMT3a DNA and further determine its binding site. Results: 1. in the body experiment, DNMT3 in the oocytes of Kaohsiung rats A was significantly lower than the control group; 2. in vitro cell experiments showed that DHT could downregulate DNMT3a mRNA in primary granulosa cells and increase the imprinting gene IGF2 mRNA; correspondingly, DHT could down regulate the expression of KGN cell DNMT3a in mRNA level, and SiRNA knockdown AR could block the downregulation effect of mRNA. Dependence reduces the expression of STAT3, and there is a binding site for STAT3 at the upstream -1118bp of the 4.DNMT3a transcription site. Conclusion: 1. in vivo Kaohsiung can reduce the expression of the key enzyme of the methylation of oocytes in rat oocytes, which may be the process of the establishment of the maternal imprint of the oocyte by Kaohsiung hormone, leading to the imprinting gene IGF2 a. In vitro experiments of 2. human granulosa cells showed that the expression of DNMT3a was down regulated from mRNA and protein levels in the 2. human granulosa cells, and this regulation was carried out through the androgen receptor pathway; the 3.DNMT3a promoter region has a reverse component of the transcription factor STAT3, and the high concentration of androgen regulation of the STAT3 protein may be It is one of the mechanisms to reduce DNMT3a expression from mRNA transcription level.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.2
本文编号：2153218
[Abstract]:The first part of the mother's pregnancy, Kaohsiung birth subgeneration follow-up, imprinted gene expression and methylation status: Observation of the growth and development of the offspring of Kaohsiung before pregnancy, blood pressure, blood lipid, blood glucose, the difference of the expression of glycometabolism related gene expression and the change of methylation, and the evaluation of the representative and table of the mother of the mother Kaohsiung. Effects of epigenetic effects. Materials and methods: a follow-up of 2002-2008 years at the hospital of Obstetrics and Gynecology, affiliated to the Medical College of Zhejiang University, which was diagnosed as Kaohsiung hormone and pregnancy success, was followed up as an experimental group and matched according to the way of pregnancy (natural pregnancy, ovulatory pregnancy, IVF-ET pregnancy), in the same period of normal natural pregnancy or The perinatal period, growth and development index, blood glucose (fasting, oral glucose tolerance test OGTT), blood lipid and blood pressure level were compared and analyzed in two groups of subgeneration perinatal period, and blood glucose and blood pressure levels were compared between the two groups. The methylation level of differentially expressed genes in the methylation region (DMR) was detected by the acid salt sequencing method. At the same time, the clinical abandoned human oocytes were collected and the oocyte maternal maternal imprinted gene IGF2 expression was detected by immunofluorescence in Kaohsiung. The results were as follows: 1. studies were followed up by 80 mothers in Kaohsiung and 146 pairs. There was no significant difference in birth weight, pregnancy week and preterm birth rate in Kaohsiung subgeneration, and there was no significant difference in the age of the two groups, body mass index (BMI), blood pressure and blood lipid levels in the two groups, and the fasting insulin (4.72 + 0.04mmol/L vs.4.60 + 0.03mmol/L, P0.05) and fasting insulin (3.58 + 0.18 u U/ml) at the birth of the mother. Vs.3.12 + 0.15 U/ml, P0.05) and HOMA insulin resistance index (0.76 + 0.04 vs.0.66 + 0.03, P0.05) were significantly higher than those of the control group. 3. of the 74 Kaohsiung group and 66 control groups had OGTT, two hours blood glucose (5.12 + 0.13mmol/Lvs.4.85 + 0.15mmol/L, P0.05) and Isle level (10.53 + 2.03 mu U/mlvs.4.72 + 1.08 U/ml,) The male progeny was significantly higher than that of the control subgeneration; the expression of IGF2 and GRB10 in the peripheral blood lymphocyte imprinting genes of 4. Kaohsiung progeny increased significantly, and the corresponding differential methylation area was significantly lower methylation. After androgens treated in vitro, the expression of IGF2 in oocytes increased significantly. Conclusion: the fasting and glucose tolerance of the offspring of the parent of the parent of Kaohsiung before pregnancy. The glucose / insulin levels were all changed in the dose test, but the blood glucose / insulin abnormal progeny was not found in the follow-up. The increased expression of IGF2 and GRB20 may be related to the change of sugar metabolism in Kaohsiung substitutes. The reduction of methylation level is the mechanism of the up-regulation of the imprinted gene expression, which suggests that mother Kaohsiung influence the representation of the offspring. Second part of the representative type of Kaohsiung rats before pregnancy, the expression of Igf2 expression and methylation of the oocytes and offspring islets of the parents: To study the glucose / insulin metabolism in the rat of Kaohsiung before pregnancy, to evaluate the risk of diabetes in Kaohsiung, and to study the expression of Igf2 in the parent and offspring islets of the parent and the offspring of the offspring. The effect of epigenetic changes on the generation effect of epigenetic changes. Materials and methods: the female Kaohsiung hormone rat model was established. The blood testosterone and the free androgen index.7 weeks before mating (6 weeks old) were used to mate Kaohsiung female rats with the normal male rats, and the normal female rats of the same age were matched with the normal male rats to get the control group. The birth weight of two groups of offspring, young (3 weeks old) and adult (8 weeks old) body weight, daily energy consumption and drinking water were measured. Glucose meter detected fasting blood glucose and glucose tolerance test, ELISA kit detected insulin level. Isolated and purified rat subgeneration islet cells and parent MII oocytes, real-time quantitative PCR detection of imprinted gene expression, The methylation status of IGF2 differential methylation area was measured by hydrogen sulphite. Results: 1. the birth weight of Kaohsiung birth progeny before pregnancy was not significantly different from that of the control group; 2. Kaohsiung progeny had increased daily drinking water and increased daily energy consumption, and the phenotypes lasted to adulthood; 3. of the Kaohsiung offspring had fasting blood glucose. Significantly higher than the control group, and 27% of the onset of diabetes (GTT30min blood glucose 11.1mmol/L). Development to adulthood, although the fasting blood glucose of the Kaohsiung offspring had no significant difference compared with the control group, but at GTT30min and 60min, the blood glucose level was still significantly higher than that of the control group, and 76% of the adult progeny still showed diabetes; 4. The level of insulin after the infancy and the injection of glucose in the juvenile of Kaohsiung was significantly lower than that in the control group. There was no significant difference between the adult fasting insulin and the control group. However, the insulin level was still significantly lower than that of the control group after the injection of glucose; 5. the Igf2 of the Kaohsiung subgeneration islet cells was significantly higher than that of the control group, and the Igf2DMR in the pancreatic islets of fetal rats was significantly higher than that of the control group. The level of 2 methylation decreased significantly; 6. the Igf2 oocyte in Kaohsiung was also highly expressed, and the level of Igf2DMR2 methylation was also significantly lower than that of the control group. More interestingly, the 3 CpG loci in the parent oocyte were corresponding to the 3 hypomethylation CpG loci of the fetal islet cells. 2. the impaired insulin release in Kaohsiung before pregnancy was the main cause of subgeneration insulin release, which was the main cause of subgeneration diabetes; 3. the expression of islet imprinting gene Igf2 in the 3. progeny of Kaohsiung was one of the mechanisms of its islet cell dysfunction; 4. of the Kaohsiung subgeneration islet islet methylation water decreased, the mechanism of Igf2 expression increased, and 5. before pregnancy. The expression of Igf2 and the change of methylation level in male oocytes. This abnormal epigenetic modification can be transferred from parent oocytes (gametes) to progeny islet cells (somatic cells). It is one of the main mechanisms of abnormal glycometabolism in the offspring of mother Kaohsiung. The third part of the regulation of the expression of methyltransferase 3A by the hormone of the hormone of Kaohsiung: the study of male The regulation of hormone on the expression of methyltransferase 3A (DNMT3a) and the molecular mechanism of androgen regulation of DNMT3a expression from two aspects in vivo and in vitro culture. Materials and methods: to obtain MII oocytes from Kaohsiung hormone model rats, and to compare the difference between the expression of DNMT3a in oocyte and normal oocyte in Kaohsiung state by immunofluorescence In vitro, in vitro, human primary granulosa cells and human KGN granulosa cells were treated with different concentrations of dihydrotestosterone (DHT), and androgen receptor (AR) small interference RNA treated cells and then added to different concentrations of DHT treatment. Real-time quantitative PCR and Western techniques were used to detect DNMT3a mRNA and protein levels in granular cells respectively. Expression changes; in the KGN granular cell line, real-time quantitative PCR and Western were used to detect the regulation of DHT on the transcription factor STAT3, and chromatin immunoprecipitation technique was used to determine whether there was a STAT3 reaction element on DNMT3a DNA and further determine its binding site. Results: 1. in the body experiment, DNMT3 in the oocytes of Kaohsiung rats A was significantly lower than the control group; 2. in vitro cell experiments showed that DHT could downregulate DNMT3a mRNA in primary granulosa cells and increase the imprinting gene IGF2 mRNA; correspondingly, DHT could down regulate the expression of KGN cell DNMT3a in mRNA level, and SiRNA knockdown AR could block the downregulation effect of mRNA. Dependence reduces the expression of STAT3, and there is a binding site for STAT3 at the upstream -1118bp of the 4.DNMT3a transcription site. Conclusion: 1. in vivo Kaohsiung can reduce the expression of the key enzyme of the methylation of oocytes in rat oocytes, which may be the process of the establishment of the maternal imprint of the oocyte by Kaohsiung hormone, leading to the imprinting gene IGF2 a. In vitro experiments of 2. human granulosa cells showed that the expression of DNMT3a was down regulated from mRNA and protein levels in the 2. human granulosa cells, and this regulation was carried out through the androgen receptor pathway; the 3.DNMT3a promoter region has a reverse component of the transcription factor STAT3, and the high concentration of androgen regulation of the STAT3 protein may be It is one of the mechanisms to reduce DNMT3a expression from mRNA transcription level.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.2
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