非编码RNA在原发性卵巢功能不全中的作用及机制研究
发布时间：2018-07-17 15:48
【摘要】：第一部分MicroRNA-22-3p在原发性卵巢功能不全患者血浆中显著下调及意义背景：长度为21-24核苷酸的非编码RNA被称为microRNA (miRNA),广泛存在于人体各种组织和体液中,在转录后水平调控基因表达。大量研究证实miRNAs不仅可以作为诊断多种癌症、糖尿病等的有效标志物,在疾病发病过程中发挥重要作用；还可以影响生殖细胞增殖和凋亡,调控排卵及黄素化部分关键过程,参与卵巢功能的多个方面。目前关于niRNAs在POI疾病的研究较少,尚不能全面阐明niRNAs在POI患者中的变化及作用。目的：本研究旨在通过μParafloTM MicroRNA芯片技术筛选POI患者血浆中差异表达的miRNAs,并在较大样本人群中验证明确miRNAs在POI患者血浆中的表达谱及其临床作用。方法：募集2012年9月至2013年12月就诊于山东大学附属生殖医院的中国汉族POI患者140例、因男方因素或输卵管因素就诊的内分泌正常对照女性140例,留取新鲜血浆。首先通过μParafloTM MicroRNA芯片技术在10例POI患者和10例对照女性血浆中筛选差异表达的miRNAs,选择差异显著的miRNAs在260例独立样本中进行验证。结果：芯片筛选出差异表达miRNAs共51个,其中22个在POI患者血浆中上调,29个下调。选择表达丰度较高的9个差异表达miRNAs (let-7b-5p、let-7c、 miR-15b-5p、miR-22-3p、miR-23a-3p、miR-23b-3p、miR-24-3p、miR-151a-5p和miR-151b)在100例独立样本中验证,发现niR-22-3p在POI患者血浆中表达量下降,其余8个miRNAs在两组人群表达无显著差异。随后我们在160例样本中验证miR-22-3p,结果显示miR-22-3p在POI患者血浆中表达显著降低(差异倍数：0.74, P0.05); ROC (receiver operating characteristic)分析提示]miR-22-3p区分POI患者与对照人群的曲线下面积(Area Under Curve, AUC)为0.668；95%confidence interval (CI):0.602-0.733;截断值(cut off value)为0.607,此截断值区分POI患者的敏感性和特异性分别是75.4%和54.6%。回归分析表明miR-22-3p是POI保护性因素(OR值：0.766,95%CI：0.643-0.912),与血清FSH水平负相关(R2=0.687,P0.05)。结论：本研究在POI患者血浆中筛选差异表达的miRNAs,发现miR-22-3p在POI患者表达量显著降低,与血清FSH水平负相关。提示miR-22-3p可能反映卵巢储备功能,是POI病理过程的一个结果。第二部分MicroRNA-379-5p调控PARP1、XRCC6在生化异常期原发性卵巢功能不全中的作用和机制研究背景：原发性卵巢功能不全病因高度异质,卵子发生障碍和卵泡耗竭加速是目前POI两种主要的致病机制假说。颗粒细胞是包绕卵母细胞的体细胞,与卵母细胞之间存在复杂的调控网络,大量研究指出颗粒细胞增殖、分化、侵袭等功能异常是卵巢卵泡耗竭的原因之一,而miRNAs可能在其中发挥重要作用。已有动物实验和体外实验表明miRNAs可以影响颗粒细胞增殖、凋亡及激素合成功能,但尚无POI患者颗粒细胞中miRNAs表达谱研究及功能研究。目的：本课题通过niRCURY?芯片技术筛选生化异常期POI患者颗粒细胞中差异表达的miRNAs;结合表达谱芯片结果,针对差异表达的miRNAs及其可能的靶基因进行功能实验,研究其对颗粒细胞生物学功能的影响和作用机制,从表观遗传角度探讨非编码RNA参与POI发生发展过程的分子机理。方法：募集2013年9月至2014年12月就诊于山东大学附属生殖医院的中国汉族生化异常阶段POI患者50例、因男方因素或输卵管因素就诊的内分泌正常对照女性50例,留取颗粒细胞。通过miRCURY?芯片技术筛选差异表达的miRNAs;与表达谱芯片联合分析选择差异最显著的miR-379-5p和其可能的靶基因PARP1、 XRCC6,通过Real-Time PCR在独立样本颗粒细胞中验证它们的表达趋势；在颗粒细胞系中过表达miR-379-5p,分别在未处理状态和紫外线(UV)和双氧水(H202)损伤后通过MTT、CCK8和EdU实验验证miR-379-5p对颗粒细胞增殖能力及损伤修复功能的影响；双荧光素酶报告系统实验等验证niR-379-5p对靶基因PARP1和XRCC6的调控及机制；沉默颗粒细胞中内源性PARP1和XRCC6,重复上述实验,明确miR-379-5p降调PARP1和XRCC6,对颗粒细胞增殖和DNA损伤修复功能的影响和作用机制。结果：芯片筛选出差异表达miRNAs共75条。我们对miRNA芯片和表达谱芯片结果进行联合分析,锁定miR-379-5p和它可能的靶基因PARPU XRCC60在60例独立样本中证实miR-379-5p在生化异常期POI患者颗粒细胞中显著上调,PARPU XRCC6在POI患者颗粒细胞中显著下调。过表达颗粒细胞中miR-379-5p可以显著抑制KGN细胞增殖,其增殖抑制作用呈时间依赖性；在UV/H2O2损伤后,过表达niR-379-5p组KGN细胞增殖抑制作用尤其显著。Luciferase和western blot实验证实miR-379-5p通过与PARPUXRCC6的3'UTR区域结合,降调PARPU XRCC6基因。特异性沉默内源性PARPU XRCC6基因对KGN细胞生物学行为可以产生与过表达miR-379-5p类似的作用,包括抑制KGN细胞增殖、UV/H2O2损伤后较低的细胞存活率和显著的增殖抑制作用等。结论：本研究首次发现POI患者颗粒细胞中显著上调的miR-379-5p可能通过降调PARPU XRCC6影响颗粒细胞增殖及损伤修复功能,参与POI疾病进程。第三部分长链非编码RNA在生化异常期原发性卵巢功能不全中的初步研究背景：长链非编码RNA (long noncoding RNA, IncRNA)是由RNA聚合酶Ⅱ转录形成、长度超过200nt的RNA分子,具有保守的剪接点和内含子,在组织和细胞中有特异的表达模式。LncRNAs可以参与染色体重塑、基因转录的激活和干扰、以及核内运输等重要调控过程,通过表观遗传沉默、转录和转录后水平调节等方式对基因表达进行调控,近年来,逐渐成为生物医学的研究热点。已有研究证实lncRNAs在癌症和神经系统疾病等人类重大疾病过程中发挥了重要的调控作用,但目前已经明确功能的lncRNAs仅有数十条,而在生殖系统疾病领域,尚无相关研究报道。目的：本研究通过芯片技术筛选并验证生化异常阶段POI患者颗粒细胞中差异表达的lncRNAs,初步探讨lncRNAs在POI患者颗粒细胞中的表达情况。方法：募集2013年9月至2014年12月就诊的中国汉族生化异常阶段POI患者50例、因男方因素或输卵管因素就诊的内分泌正常对照女性50例,留取颗粒细胞。通过LncRNA芯片技术在10例POI患者与10例对照女性颗粒细胞中筛选差异表达的lncRNAs和mRNAs;根据表达谱芯片Gene ontology和KEGG pathway分析结果,对差异表达的lncRNAs和mRNAs进行共表达网络分析(co-expression networks),按照相对表达丰度、变化倍数及序列信息,选择处于核心位置、与重要且差异表达的基因存在相关关系的14条lncRNAs在60例独立样本中进行验证。结果：芯片结果发现差异表达lncRNAs序列677条。Real-Time PCR实验证实其中：TCONS 00010009、TCONS 00014547、NR 040662.1、ENST00000520306、ENST00000420313、ENST00000526225在POI患者颗粒细胞中显著下调。生物信息学分析表明它们全部属于lincRNAs,其周围均分布有许多功能重要的编码基因,尤其DNA损伤修复基因XRCC4和MSH5分别位于TCONS_00010009和NR 040662附近不足300kb处,提示我们这些差异表达的lincRNAs可能通过调控周围的共表达基因参与POI疾病。结论：本研究首次通过Arraystar Human IncRNA芯片对颗粒细胞OncRNAs特征进行初步研究。生化异常阶段POI患者颗粒细胞中存在较多差异表达的LncRNA,可能与疾病相关。
[Abstract]:The first part is the significant down-regulation and significance of MicroRNA-22-3p in the plasma of patients with primary ovarian insufficiency: the non coded RNA with a length of 21-24 nucleotides is called microRNA (miRNA), which widely exists in various tissues and body fluids of the human body and regulates gene expression at post transcriptional level. A large number of studies have confirmed that miRNAs can not only be used as a diagnostic multiple. The effective markers of cancer and diabetes, such as diabetes, play an important role in the pathogenesis of disease; it can also affect the proliferation and apoptosis of germ cells, regulate the key processes of ovulation and yellowing, and participate in many aspects of ovarian function. At present, there are few studies on niRNAs in the disease of POI, and there is no comprehensive explanation of niRNAs in POI patients. Objective: the purpose of this study was to screen the differential expression of miRNAs in the plasma of POI patients by micron ParafloTM MicroRNA chip technology, and to verify the expression and clinical effect of miRNAs in the plasma of POI patients in a large sample population. Methods: to collect the Reproductive Medicine Affiliated to the Shandong University from September 2012 to December 2013. 140 cases of POI patients in Chinese Han nationality, 140 cases of normal control women with endocrine and fallopian tube factors, 140 cases of fresh plasma were left. The differential expression of miRNAs was screened in 10 cases of POI patients and 10 cases of control female plasma by micron MicroRNA chip technique. The difference of significant miRNAs was selected in 260 independent samples. Results: the chip screened a total of 51 differentially expressed miRNAs, of which 22 were up-regulated and 29 down-regulated in the plasma of POI patients. 9 differential expressions of miRNAs (let-7b-5p, Let-7c, miR-15b-5p, miR-22-3p, miR-23a-3p, miR-23b-3p, miR-24-3p, miR-151a-5p and miR-151b) were verified in 100 independent samples. The expression of R-22-3p in the plasma of POI patients decreased and the other 8 miRNAs expressed no significant difference in the two groups. Then we tested the miR-22-3p in 160 samples. The results showed that the expression of miR-22-3p in the plasma of POI patients was significantly reduced (the difference Multiplier: 0.74, P0.05); ROC (receiver operating characteristic) analysis suggested]miR-22-3p area The area under the curve (Area Under Curve, AUC) in the POI patients and the control group was 0.668, 95%confidence interval (CI): 0.602-0.733, and the truncated value (cut off value) was 0.607. 643-0.912) and negative correlation with serum FSH level (R2=0.687, P0.05). Conclusion: This study screened the differential expression of miRNAs in the plasma of POI patients. It was found that the expression of miR-22-3p in POI patients was significantly lower and negatively correlated with the level of serum FSH. It suggested that miR-22-3p may reflect the ovarian reserve power, which is a result of POI pathological process. Second part MicroRNA. -379-5p regulates the role and mechanism of PARP1 and XRCC6 in primary ovarian dysfunction during biochemical abnormal stages: the high heterogeneity of the etiology of primary ovarian dysfunction, the disorder of oogenesis and the acceleration of follicle exhaustion are the two main pathogenesis hypothesis of POI. Granulosa cells are somatic cells wrapped around oocytes and oocytes. There is a complex regulatory network. A large number of studies have pointed out that the proliferation, differentiation and invasion of granulosa cells are one of the reasons for ovarian follicle depletion, and miRNAs may play an important role in it. Animal experiments and in vitro experiments have shown that miRNAs can affect granulosa cell proliferation, apoptosis and hormone synthesis, but there is no POI patient yet. Study and function study of miRNAs expression in granulosa cells. Objective: to screen the differential expression of miRNAs in granulosa cells of patients with POI in biochemical abnormal phase by niRCURY chip technology, and to study the granulosa cell biology by combining the results of the expression spectrum chip to the differentially expressed miRNAs and its possible target genes. The effect and mechanism of function, from the epigenetic point of view, to explore the molecular mechanism of the non coded RNA participating in the development of POI. Methods: 50 cases of POI patients were collected from September 2013 to December 2014 in the affiliated reproductive Hospital of Shandong University. 50 women compared with 50 women, retained granular cells. The differentially expressed miRNAs was screened by miRCURY chip technology; the most significant difference was selected with the expression spectrum chip to select the most significant miR-379-5p and its possible target gene PARP1, XRCC6. The expression trend was verified by Real-Time PCR in the independent sample granulosa cells, and the table in the granular cell line was overexpressed. The effects of miR-379-5p on the proliferation and repair function of granulosa cells were verified by MTT, CCK8 and EdU experiments after the untreated state and ultraviolet (UV) and hydrogen peroxide (H202) damage, respectively. The regulation and mechanism of niR-379-5p on the target gene PARP1 and XRCC6 were verified by the double luciferase reporter system experiment, and the silencing of granular cells was verified by the double luciferase reporter system experiment. Endogenous PARP1 and XRCC6, repeat the above experiments to determine the effect and mechanism of miR-379-5p downfall PARP1 and XRCC6 on the proliferation of granulosa cells and the function of DNA damage repair. Results: the chip screened a total of 75 differentially expressed miRNAs strips. We combined the results of miRNA chip and expression spectrum chip, locked miR-379-5p and its possible target. In 60 independent samples, gene PARPU XRCC60 showed that miR-379-5p was significantly up-regulated in granulosa cells of POI patients with abnormal biochemical phase, and PARPU XRCC6 was significantly down-regulated in granulosa cells of POI patients. MiR-379-5p could significantly inhibit the proliferation of KGN cells in the overexpressed granulosa cells, and its proliferation inhibition was time dependent; after UV/H2O2 damage, a table was overexpressed. The proliferation inhibition effect of KGN cells in the niR-379-5p group was particularly significant.Luciferase and Western blot experiments confirmed that miR-379-5p could reduce the PARPU XRCC6 gene by binding to the 3'UTR region of PARPUXRCC6. N cell proliferation, lower cell survival rate and significant proliferation inhibition after UV/H2O2 injury. Conclusion: This study first found that the significant up regulation of miR-379-5p in granulosa cells of POI patients may be involved in the function of granulosa cell proliferation and injury repair by lowering the modulation of PARPU XRCC6 in the POI disease process. The third part of the long chain non coded RNA is in the process. Primary research background in primary ovarian dysfunction in biochemical abnormal phase: long chain non coded RNA (long noncoding RNA, IncRNA) is transcribed by RNA polymerase II, with a RNA molecule in length exceeding 200nt, with a conservative splicing point and intron, and a specific expression pattern in tissues and cells that.LncRNAs can be involved in chromosome remodeling. The activation and interference of gene transcription, as well as important regulatory processes such as intra nuclear transport, regulate gene expression through epigenetic silence, transcriptional and post transcriptional regulation. In recent years, it has gradually become a research hotspot in biomedicine. LncRNAs has been proved to be in the process of human major diseases such as cancer and nervous system diseases. It has played an important role in regulation and control, but there are only dozens of lncRNAs clearly defined functions, and there are no related reports in the field of reproductive system disease. Objective: This study screened and verified the differential expression of lncRNAs in granulosa cells of patients with POI in biochemical abnormal stage by chip technology, and preliminarily explored the granulosa cells of lncRNAs in POI patients. Methods: 50 cases of POI patients were collected from September 2013 to December 2014 in the Chinese Han nationality biochemical abnormal stage. 50 cases of endocrine normal control women were treated with male and fallopian factors and 50 cases of granulosa cells were left. The difference table was screened in 10 cases of POI patients and 10 control female granulosa cells through the technique of POI chip. LncRNAs and mRNAs, according to the analysis results of Gene ontology and KEGG pathway on the expression spectrum chip, the co expression network analysis (co-expression networks) of the differentially expressed lncRNAs and mRNAs, according to the relative expression abundance, the multiplier and sequence information, is selected at the core position and is related to the important and differentially expressed genes. 14 lncRNAs were verified in 60 independent samples. Results: the results showed that 677.Real-Time PCR experiments of differential expression lncRNAs sequence showed that TCONS 00010009, TCONS 00014547, NR 40662.1, ENST00000520306, ENST00000420313, ENST00000526225 were significantly downregulated in POI patient granulosa cells. Bioinformatics analysis table All of them belong to lincRNAs, and there are many important coding genes around them. Especially, the DNA damage repair gene XRCC4 and MSH5 are located at the deficiency of 300KB near TCONS_00010009 and NR 040662, suggesting that these differentially expressed lincRNAs may participate in the POI disease by regulating the surrounding co expression genes. The initial study on the OncRNAs characteristics of granulosa cells by Arraystar Human IncRNA chip is the first time. There are many differentially expressed LncRNA in the granulosa cells of POI patients at the biochemical abnormal stage, which may be related to the disease.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R711.75
[Abstract]:The first part is the significant down-regulation and significance of MicroRNA-22-3p in the plasma of patients with primary ovarian insufficiency: the non coded RNA with a length of 21-24 nucleotides is called microRNA (miRNA), which widely exists in various tissues and body fluids of the human body and regulates gene expression at post transcriptional level. A large number of studies have confirmed that miRNAs can not only be used as a diagnostic multiple. The effective markers of cancer and diabetes, such as diabetes, play an important role in the pathogenesis of disease; it can also affect the proliferation and apoptosis of germ cells, regulate the key processes of ovulation and yellowing, and participate in many aspects of ovarian function. At present, there are few studies on niRNAs in the disease of POI, and there is no comprehensive explanation of niRNAs in POI patients. Objective: the purpose of this study was to screen the differential expression of miRNAs in the plasma of POI patients by micron ParafloTM MicroRNA chip technology, and to verify the expression and clinical effect of miRNAs in the plasma of POI patients in a large sample population. Methods: to collect the Reproductive Medicine Affiliated to the Shandong University from September 2012 to December 2013. 140 cases of POI patients in Chinese Han nationality, 140 cases of normal control women with endocrine and fallopian tube factors, 140 cases of fresh plasma were left. The differential expression of miRNAs was screened in 10 cases of POI patients and 10 cases of control female plasma by micron MicroRNA chip technique. The difference of significant miRNAs was selected in 260 independent samples. Results: the chip screened a total of 51 differentially expressed miRNAs, of which 22 were up-regulated and 29 down-regulated in the plasma of POI patients. 9 differential expressions of miRNAs (let-7b-5p, Let-7c, miR-15b-5p, miR-22-3p, miR-23a-3p, miR-23b-3p, miR-24-3p, miR-151a-5p and miR-151b) were verified in 100 independent samples. The expression of R-22-3p in the plasma of POI patients decreased and the other 8 miRNAs expressed no significant difference in the two groups. Then we tested the miR-22-3p in 160 samples. The results showed that the expression of miR-22-3p in the plasma of POI patients was significantly reduced (the difference Multiplier: 0.74, P0.05); ROC (receiver operating characteristic) analysis suggested]miR-22-3p area The area under the curve (Area Under Curve, AUC) in the POI patients and the control group was 0.668, 95%confidence interval (CI): 0.602-0.733, and the truncated value (cut off value) was 0.607. 643-0.912) and negative correlation with serum FSH level (R2=0.687, P0.05). Conclusion: This study screened the differential expression of miRNAs in the plasma of POI patients. It was found that the expression of miR-22-3p in POI patients was significantly lower and negatively correlated with the level of serum FSH. It suggested that miR-22-3p may reflect the ovarian reserve power, which is a result of POI pathological process. Second part MicroRNA. -379-5p regulates the role and mechanism of PARP1 and XRCC6 in primary ovarian dysfunction during biochemical abnormal stages: the high heterogeneity of the etiology of primary ovarian dysfunction, the disorder of oogenesis and the acceleration of follicle exhaustion are the two main pathogenesis hypothesis of POI. Granulosa cells are somatic cells wrapped around oocytes and oocytes. There is a complex regulatory network. A large number of studies have pointed out that the proliferation, differentiation and invasion of granulosa cells are one of the reasons for ovarian follicle depletion, and miRNAs may play an important role in it. Animal experiments and in vitro experiments have shown that miRNAs can affect granulosa cell proliferation, apoptosis and hormone synthesis, but there is no POI patient yet. Study and function study of miRNAs expression in granulosa cells. Objective: to screen the differential expression of miRNAs in granulosa cells of patients with POI in biochemical abnormal phase by niRCURY chip technology, and to study the granulosa cell biology by combining the results of the expression spectrum chip to the differentially expressed miRNAs and its possible target genes. The effect and mechanism of function, from the epigenetic point of view, to explore the molecular mechanism of the non coded RNA participating in the development of POI. Methods: 50 cases of POI patients were collected from September 2013 to December 2014 in the affiliated reproductive Hospital of Shandong University. 50 women compared with 50 women, retained granular cells. The differentially expressed miRNAs was screened by miRCURY chip technology; the most significant difference was selected with the expression spectrum chip to select the most significant miR-379-5p and its possible target gene PARP1, XRCC6. The expression trend was verified by Real-Time PCR in the independent sample granulosa cells, and the table in the granular cell line was overexpressed. The effects of miR-379-5p on the proliferation and repair function of granulosa cells were verified by MTT, CCK8 and EdU experiments after the untreated state and ultraviolet (UV) and hydrogen peroxide (H202) damage, respectively. The regulation and mechanism of niR-379-5p on the target gene PARP1 and XRCC6 were verified by the double luciferase reporter system experiment, and the silencing of granular cells was verified by the double luciferase reporter system experiment. Endogenous PARP1 and XRCC6, repeat the above experiments to determine the effect and mechanism of miR-379-5p downfall PARP1 and XRCC6 on the proliferation of granulosa cells and the function of DNA damage repair. Results: the chip screened a total of 75 differentially expressed miRNAs strips. We combined the results of miRNA chip and expression spectrum chip, locked miR-379-5p and its possible target. In 60 independent samples, gene PARPU XRCC60 showed that miR-379-5p was significantly up-regulated in granulosa cells of POI patients with abnormal biochemical phase, and PARPU XRCC6 was significantly down-regulated in granulosa cells of POI patients. MiR-379-5p could significantly inhibit the proliferation of KGN cells in the overexpressed granulosa cells, and its proliferation inhibition was time dependent; after UV/H2O2 damage, a table was overexpressed. The proliferation inhibition effect of KGN cells in the niR-379-5p group was particularly significant.Luciferase and Western blot experiments confirmed that miR-379-5p could reduce the PARPU XRCC6 gene by binding to the 3'UTR region of PARPUXRCC6. N cell proliferation, lower cell survival rate and significant proliferation inhibition after UV/H2O2 injury. Conclusion: This study first found that the significant up regulation of miR-379-5p in granulosa cells of POI patients may be involved in the function of granulosa cell proliferation and injury repair by lowering the modulation of PARPU XRCC6 in the POI disease process. The third part of the long chain non coded RNA is in the process. Primary research background in primary ovarian dysfunction in biochemical abnormal phase: long chain non coded RNA (long noncoding RNA, IncRNA) is transcribed by RNA polymerase II, with a RNA molecule in length exceeding 200nt, with a conservative splicing point and intron, and a specific expression pattern in tissues and cells that.LncRNAs can be involved in chromosome remodeling. The activation and interference of gene transcription, as well as important regulatory processes such as intra nuclear transport, regulate gene expression through epigenetic silence, transcriptional and post transcriptional regulation. In recent years, it has gradually become a research hotspot in biomedicine. LncRNAs has been proved to be in the process of human major diseases such as cancer and nervous system diseases. It has played an important role in regulation and control, but there are only dozens of lncRNAs clearly defined functions, and there are no related reports in the field of reproductive system disease. Objective: This study screened and verified the differential expression of lncRNAs in granulosa cells of patients with POI in biochemical abnormal stage by chip technology, and preliminarily explored the granulosa cells of lncRNAs in POI patients. Methods: 50 cases of POI patients were collected from September 2013 to December 2014 in the Chinese Han nationality biochemical abnormal stage. 50 cases of endocrine normal control women were treated with male and fallopian factors and 50 cases of granulosa cells were left. The difference table was screened in 10 cases of POI patients and 10 control female granulosa cells through the technique of POI chip. LncRNAs and mRNAs, according to the analysis results of Gene ontology and KEGG pathway on the expression spectrum chip, the co expression network analysis (co-expression networks) of the differentially expressed lncRNAs and mRNAs, according to the relative expression abundance, the multiplier and sequence information, is selected at the core position and is related to the important and differentially expressed genes. 14 lncRNAs were verified in 60 independent samples. Results: the results showed that 677.Real-Time PCR experiments of differential expression lncRNAs sequence showed that TCONS 00010009, TCONS 00014547, NR 40662.1, ENST00000520306, ENST00000420313, ENST00000526225 were significantly downregulated in POI patient granulosa cells. Bioinformatics analysis table All of them belong to lincRNAs, and there are many important coding genes around them. Especially, the DNA damage repair gene XRCC4 and MSH5 are located at the deficiency of 300KB near TCONS_00010009 and NR 040662, suggesting that these differentially expressed lincRNAs may participate in the POI disease by regulating the surrounding co expression genes. The initial study on the OncRNAs characteristics of granulosa cells by Arraystar Human IncRNA chip is the first time. There are many differentially expressed LncRNA in the granulosa cells of POI patients at the biochemical abnormal stage, which may be related to the disease.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R711.75
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