转录组分析揭示PCOS炎症和蛋白质合成基因的失调-动脉网

Transcriptome profiling reveals dysregulation of inflammatory and protein synthesis genes in PCOS

Nature 等信源发布 2024-07-18 16:53

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AbstractTo analyze the differential expression genes of polycystic ovary syndrome (PCOS), clarify their functions and pathways, as well as the protein–protein interaction network, identify HUB genes, and explore the pathological mechanism. PCOS microarray datasets were screened from the GEO database.

摘要分析多囊卵巢综合征（PCOS）的差异表达基因，阐明其功能和途径，以及蛋白质-蛋白质相互作用网络，鉴定中枢基因，探讨其病理机制。从GEO数据库中筛选PCOS微阵列数据集。

Common differentially expressed genes (co-DEGs) were obtained using GEO2R and Venn analysis. Enrichment and pathway analyses were conducted using the DAVID online tool, with results presented in bubble charts. Protein–protein interaction analysis was performed using the STRING tool. HUB genes were identified using Cytoscape software and further interpreted with the assistance of the GeneCards database.

使用GEO2R和Venn分析获得了常见的差异表达基因（co-DEG）。使用DAVID在线工具进行富集和途径分析，结果显示在气泡图中。使用STRING工具进行蛋白质-蛋白质相互作用分析。使用Cytoscape软件鉴定中枢基因，并在GeneCards数据库的帮助下进一步解释。

A total of two sets of co-DEGs (108 and 102), key proteins (15 and 55), and hub genes (10 and 10) were obtained. The co-DEGs: (1) regulated inflammatory responses and extracellular matrix, TNF, and IL-17 signaling pathways; (2) regulated ribosomes and protein translation, ribosome and immune pathways.

总共获得了两组co-DEG（108和102），关键蛋白（15和55）和中枢基因（10和10）。共DEGs：（1）调节炎症反应和细胞外基质，TNF和IL-17信号通路；（2）调节核糖体和蛋白质翻译，核糖体和免疫途径。

The key proteins: (1) regulated inflammation, immunity, transcription, matrix metabolism, proliferation/differentiation, energy, and repair; (2) regulated ubiquitination, enzymes, companion proteins, respiratory chain components, and fusion proteins. The Hub genes: (1) encoded transcription factors and cytokines, playing vital roles in development and proliferation; (2) encoded ribosomes and protein synthesis, influencing hormone and protein synthesis, associated with development and infertility.

关键蛋白：（1）调节炎症，免疫，转录，基质代谢，增殖/分化，能量和修复；（2）调节泛素化，酶，伴侣蛋白，呼吸链成分和融合蛋白。中枢基因：（1）编码转录因子和细胞因子，在发育和增殖中起着至关重要的作用；（2）编码的核糖体和蛋白质合成，影响激素和蛋白质合成，与发育和不育有关。

The dysregulated expression of inflammation and protein synthesis genes in PCOS may be the key mechanism underlying its onset and progression..

PCOS中炎症和蛋白质合成基因的表达失调可能是其发病和进展的关键机制。。

IntroductionPolycystic ovary syndrome (PCOS) is a prevalent gynecological reproductive disorder affecting 4–7% of women globally, characterized by prolonged anovulation, hyperandrogenism, and polycystic ovaries. These features are not only closely associated with infertility but may also significantly impact the quality of life and mental health1.

简介多囊卵巢综合征（PCOS）是一种普遍存在的妇科生殖疾病，影响全球4-7%的女性，其特征是长期无排卵，雄激素过多和多囊卵巢。。

Although various treatment methods have been employed, there remains room for improvement in their efficacy and approaches2. Elucidating the intricate pathophysiological mechanisms underlying PCOS is crucial for identifying more effective therapies, Which represents an urgent biomedical research goal with significant clinical implications.In recent years, rapid advances in genetic analysis have led to significant progress in deciphering the genetic architecture of PCOS pathogenesis.

虽然已经采用了各种治疗方法，但其疗效和方法仍有改进的空间2。阐明PCOS背后复杂的病理生理机制对于确定更有效的疗法至关重要，这代表了一个迫切的生物医学研究目标，具有重要的临床意义。近年来，遗传分析的快速发展在破译PCOS发病机理的遗传结构方面取得了重大进展。

Various PCOS-associated genetic loci have been identified, including gene mutations, polymorphisms3,4, and potential epigenetic effects5. These genetic variations implicate critical biological processes like androgen metabolism and insulin signaling, providing vital clues to unraveling PCOS pathophysiology5,6.

已经鉴定了各种PCOS相关的基因位点，包括基因突变，多态性3,4和潜在的表观遗传效应5。这些遗传变异涉及雄激素代谢和胰岛素信号传导等关键生物学过程，为揭示PCOS病理生理学提供了重要线索5,6。

However, the complex multifactorial etiology of PCOS poses challenges for elucidation by single gene studies alone. Heterogeneous genetic backgrounds among populations lead to inconsistent findings, and gene regulatory networks underlying PCOS remain incompletely defined7. Therefore, a holistic, systematic approach is imperative, aggregating extensive sample datasets to uncover common PCOS-associated differentially expressed genes (co-DEGs), delineate their correlations with clinical presentation, and lay a scientific foundation for precise diagnosis and treatment5.This study utilized publicly available information from the GEO database to sc.

然而，PCOS复杂的多因素病因对单基因研究的阐明提出了挑战。人群之间的异质遗传背景导致不一致的发现，PCOS的基因调控网络仍未完全定义7。因此，必须采用整体，系统的方法，汇总广泛的样本数据集，以发现常见的PCOS相关差异表达基因（co-DEGs），描述它们与临床表现的相关性，并为精确诊断和治疗奠定科学基础5。本研究利用了从GEO数据库到sc的公开信息。

Proteins with connecting nodes ≥ 5: There are 15 such proteins whose functions are detailed in Supplementary Table 1. These proteins are closely related to immune-inflammatory responses, tissue damage, and repair processes. Specifically, they regulate inflammation, gene expression, immune cell function, connective tissue and extracellular matrix metabolism, cell proliferation and differentiation, and intracellular metabolism..

具有连接节点≥5的蛋白质：有15种这样的蛋白质，其功能详见补充表1。这些蛋白质与免疫炎症反应，组织损伤和修复过程密切相关。具体而言，它们调节炎症，基因表达，免疫细胞功能，结缔组织和细胞外基质代谢，细胞增殖和分化以及细胞内代谢。。

Functions of 10 dark-colored node proteins: Refer to Supplementary Table 3. These crucial proteins involve various processes, such as antioxidative stress, metabolic regulation, and cell cycle control. Abnormalities in these proteins can lead to oxidative damage, metabolic disorders, and cell cycle dysregulation.

10种深色节点蛋白的功能：参见补充表3。。这些蛋白质的异常可导致氧化损伤，代谢紊乱和细胞周期失调。

For example, PRDX6 (Peroxiredoxin) is an antioxidant protein that reduces hydrogen peroxide and lipid peroxides, protecting cells from oxidative damage. It is also involved in phosphatidylcholine synthesis. ETS2, a transcription factor, activates the transcription of various genes that regulate cell proliferation and differentiation.

例如，PRDX6（过氧化物氧还蛋白）是一种抗氧化蛋白，可减少过氧化氢和脂质过氧化物，保护细胞免受氧化损伤。它还参与磷脂酰胆碱的合成。ETS2是一种转录因子，可激活调节细胞增殖和分化的各种基因的转录。

IFIT3 is an antiviral protein that inhibits viral replication and enhances antiviral responses. CYB5A (Cytochrome b5) participates in electron transfer, supporting redox reactions. GAMT is involved in the creatine synthesis pathway, crucial for nervous system development. FBXO21 may act as part of a ubiquitin ligase complex, which regulates protein ubiquitination and degradation.

IFIT3是一种抗病毒蛋白，可抑制病毒复制并增强抗病毒反应。CYB5A（细胞色素b5）参与电子转移，支持氧化还原反应。GAMT参与肌酸合成途径，对神经系统发育至关重要。FBXO21可以作为泛素连接酶复合物的一部分，该复合物调节蛋白质的泛素化和降解。

SIK1, a serine/threonine kinase, regulates the cell cycle and gluconeogenesis and acts as a tumor suppressor; SPAG4 and JUNB regulate cell proliferation and differentiation..

SIK1是一种丝氨酸/苏氨酸激酶，可调节细胞周期和糖异生，并可作为肿瘤抑制剂；SPAG4和JUNB调节细胞增殖和分化。。

Functional and Pathway Enrichment (Supplementary Table 5): “Response to steroid hormone” enrichment suggests co-DEGs play roles in response to steroid hormones. Cellular component enrichment in “Extracellular matrix” and “Collagen-containing extracellular matrix” indicates that co-DEGs are related to the structure and function of the extracellular matrix, especially collagen-containing matrices.

功能和途径富集（补充表5）：“对类固醇激素的反应”富集表明co-DEGs在类固醇激素反应中发挥作用。“细胞外基质”和“含胶原蛋白的细胞外基质”中的细胞成分富集表明，co-DEGs与细胞外基质的结构和功能有关，尤其是含胶原蛋白的基质。

“TNF signaling pathway” enrichment suggests co-DEGs are involved in TNF signaling, potentially related to inflammatory and immune responses. These enrichment results are meaningful for understanding PCOS's onset, progression, and treatment..

“TNF信号通路”富集表明co-DEGs参与TNF信号传导，可能与炎症和免疫反应有关。这些富集结果对于了解PCOS的发病，进展和治疗具有重要意义。。

Group 2The average node degree is 29.7. A high average local clustering coefficient (near 0.7) suggests tight connections. The clustering in the PPI network is highly significant, meaning biologically meaningful connections. The proteins are involved in complex and close interactions, participating in critical biological processes or signaling pathways, and are central components of critical pathways or regulatory networks..

第2组平均节点度为29.7。较高的平均局部聚类系数（接近0.7）表明联系紧密。PPI网络中的聚类非常重要，这意味着具有生物学意义的联系。这些蛋白质参与复杂而密切的相互作用，参与关键的生物过程或信号通路，是关键通路或调控网络的核心组成部分。。

Connecting nodes ≥ 20: The 55 proteins are detailed in Supplementary Table 2. These proteins are involved in fundamental cellular activities like gene expression, protein synthesis, metabolism, protein folding, degradation, and mitochondrial functions. They include ribosomal proteins (e.g., RPL, RPS) which are part of the ribosome and responsible for protein synthesis, proteins involved in protein synthesis (e.g., EEF1B2, EEF1G), enzymes involved in cellular metabolism (e.g., GAPDH, TPI1, NME1/2), molecular chaperones like HSP90AB1, components of mitochondrial respiratory chain complexes (e.g., COX7C, ATP5F1B) or protein degradation complexes (e.g., PSMA6), and fusion proteins (e.g., RPL17-C18orf32, NME1-NME2, RPS10-NUDT3)..

连接节点≥20:55种蛋白质详见补充表2。这些蛋白质参与基本的细胞活动，如基因表达，蛋白质合成，代谢，蛋白质折叠，降解和线粒体功能。它们包括核糖体蛋白（如RPL、RPS），它们是核糖体的一部分，负责蛋白质合成，参与蛋白质合成的蛋白质（如EEF1B2、EEF1G），参与细胞代谢的酶（如GAPDH、TPI1、NME1/2），分子伴侣如HSP90AB1，线粒体呼吸链复合物（如COX7C、ATP5F1B）或蛋白质降解复合物（如PSMA6）的成分，以及融合蛋白（如RPL17-C18orf32、NME1-NME2、RPS10-NUDT3）。。

Functions of 16 dark-colored node proteins: Refer to Supplementary Table 4. They are related to nucleotide metabolism, protein production, cytoskeletal processes, etc. Abnormalities in these proteins could lead to metabolic disorders, coagulation dysfunctions, and cell motility disorders. Ribosomal proteins (e.g., RPS27, RPL36, RPL17, RPS11, RPL24, RPL38) are involved in ribosome assembly, post-transcriptional modifications of mRNA, and protein translation.

16种深色节点蛋白的功能：参见补充表4。它们与核苷酸代谢，蛋白质产生，细胞骨架过程等有关。这些蛋白质的异常可能导致代谢紊乱，凝血功能障碍和细胞运动障碍。核糖体蛋白（例如RPS27，RPL36，RPL17，RPS11，RPL24，RPL38）参与核糖体组装，mRNA的转录后修饰和蛋白质翻译。

SF3B5, a part of the spliceosome, is involved in pre-mRNA splicing. NME2 is involved in nucleotide synthesis and regulates Rho signaling and MYC gene expression. RPS14 is a structural component of the ribosome. TFPI (Tissue Factor Pathway Inhibitor) directly inhibits coagulation factor X (Xa) in coagulation regulation.

SF3B5是剪接体的一部分，参与前mRNA剪接。NME2参与核苷酸合成并调节Rho信号传导和MYC基因表达。RPS14是核糖体的结构成分。TFPI（组织因子途径抑制剂）在凝血调节中直接抑制凝血因子X（Xa）。

TMSB10 is involved in cytoskeletal reorganization. ZYX, an adhesion protein, mediates gene expression changes triggered by adhesion stimuli. TUBA1C, a major component of microtubules, and CETN2 are involved in the structure and function of the microtubule organizing center..

TMSB10参与细胞骨架重组。ZYX是一种粘附蛋白，介导由粘附刺激引发的基因表达变化。TUBA1C是微管的主要成分，CETN2参与微管组织中心的结构和功能。。

Functional and Pathway Enrichment (Supplementary Table 6): Biological processes like “Cytoplasmic translation,” “Ribosomal small subunit assembly,” “Ribosomal large subunit assembly,” “Ribosome assembly,” “Translation,” etc., indicate co-DGEs play significant roles in protein synthesis and metabolism.

功能和途径富集（补充表6）：诸如“细胞质翻译”，“核糖体小亚基组装”，“核糖体大亚基组装”，“核糖体组装”，“翻译”等生物过程表明共DGEs在蛋白质合成和代谢中起重要作用。

Other enriched biological processes are related to nucleotide biosynthesis and metabolism, such as “UTP biosynthetic process,” “GTP biosynthetic process,” “CTP biosynthetic process,” “Nucleoside diphosphate phosphorylation,” “Purine ribonucleoside triphosphate biosynthesis,” etc..

其他富集的生物过程与核苷酸的生物合成和代谢有关，例如“UTP生物合成过程”，“GTP生物合成过程”，“CTP生物合成过程”，“核苷二磷酸磷酸化”，“嘌呤核糖核苷三磷酸生物合成”等。。

The molecular function enrichment reflects vigorous tissue metabolism and growth, with active gene expression regulation, protein synthesis, structural formation processes, and intercellular adhesion interactions. For example, enrichment in the structural constituent of the ribosome and rRNA binding indicates enhanced protein translation and ribosome assembly activities.

分子功能的富集反映了活跃的组织代谢和生长，具有活跃的基因表达调控，蛋白质合成，结构形成过程和细胞间粘附相互作用。例如，核糖体结构成分的富集和rRNA结合表明蛋白质翻译和核糖体组装活性增强。

Structural molecule activity enrichment suggests increased activities in forming cellular structures and maintaining cell morphology.Cell component enrichment includes a. “Ribosomal subunit,” “Polysome,” “Large ribosomal subunit,” “Cytosolic small ribosomal subunit,” etc., indicating the network's involvement in protein synthesis and processing.

结构分子活性富集表明形成细胞结构和维持细胞形态的活性增加。。

b. “Focal adhesion” suggests participation in transporting proteins, lipids, and other molecules. Overall, cell component enrichment results relate to protein synthesis. “GAIT complex” has a high strength (2.01), implying biological significance, and a very low FDR value, indicating its statistical significance.

b、 “粘着斑”表明参与运输蛋白质，脂质和其他分子。总体而言，细胞成分富集结果与蛋白质合成有关。“步态复合体”具有很高的强度（2.01），意味着生物学意义，而FDR值非常低，表明其统计学意义。

Entries such as “Cytosolic ribosome” and “Large ribosomal subunit” have a relatively high number of genes and very low FDR values, suggesting these genes may be essential in this network.KEGG pathways (Supplementary Table 7): a. The “Ribosome” pathway involves 39 genes, with an intensity of 1.79 and a very low FDR (6.73e-54), indicating its extreme importance.

诸如“胞质核糖体”和“大核糖体亚基”的条目具有相对较高的基因数量和非常低的FDR值，表明这些基因在该网络中可能是必需的.KEGG途径（补充表7）：a.“核糖体”途径涉及39个基因，强度为1.79，FDR非常低（6.73e-54），表明其极端重要性。

The ribosome, as the site of protein synthesis, in conjunction with other pathways, may be related to neuronal repair and regeneration. b. The “Oxidative phosphorylation” pathway includes five genes, with an intensity of 0.9 and an FDR of 0.0228, highlighting its importance. It is the main pathway for cellular energy production, and its enrichment suggests an upregulation of mitochondrial function,.

核糖体作为蛋白质合成的位点，与其他途径一起，可能与神经元修复和再生有关。b、 “氧化磷酸化”途径包括五个基因，强度为0.9，FDR为0.0228，突出了其重要性。它是细胞能量产生的主要途径，其富集表明线粒体功能上调，。

Data availability

数据可用性

The datasets generated and analyzed during the current study are available in the Mendeley repository (https://data.mendeley.com/datasets/3n3xz759hb/1) and from the corresponding author upon reasonable request.

在当前研究期间生成和分析的数据集可在Mendeley repository中找到(https://data.mendeley.com/datasets/3n3xz759hb/1)并根据合理的要求从通讯作者那里。

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Download referencesAcknowledgementsThanks to the other members of the laboratory for their assistance, the project foundation for their financial support, and the institution for their support. We would like to express our sincere gratitude to the Gene Expression Omnibus (GEO) database for providing a platform for data sharing and to the contributors of the datasets used in this study (GSE155489, GSE226146, and GSE159466).

下载参考文献致谢感谢实验室的其他成员的帮助，项目基金会的财政支持以及机构的支持。我们衷心感谢Gene Expression Omnibus（GEO）数据库为数据共享提供了平台，并感谢本研究中使用的数据集的贡献者（GSE155489，GSE226146和GSE159466）。

Their willingness to share their valuable data has made this research possible.FundingThis work was supported by Military Key Discipline Construction Projects of China (HL21JD1206) and China Medical Board (CMB21-428) .Author informationAuthors and AffiliationsObstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, ChinaXilian Li, Bingsi Gao, Xin Li & Xian XiaTeaching and Research Support Center, Naval Medical University, Shanghai, 200433, ChinaBiao GaoAuthorsXilian LiView author publicationsYou can also search for this author in.

他们愿意分享宝贵的数据，这使得这项研究成为可能。资助这项工作得到了中国军事重点学科建设项目（HL21JD1206）和中国医学委员会（CMB21-428）的支持。作者信息作者和附属机构复旦大学妇产科医院，上海，200011，中国李希莲，高炳思，李新霞海军医科大学教学与研究支持中心，上海，200433，高国标作者西莲LiView作者出版物您也可以在中搜索作者。

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PubMed Google ScholarContributionsXiliang Li: Conceptualization, Methodology, Software, Investigation, Formal Analysis, Writing Original Draft; Biao Gao: Conceptualization, Funding Acquisition, Methodology, Software, Investigation, Formal Analysis, Writing Original Draft; Bingsi Gao: Data Curation, Writing Original Draft; Xin Li: Conceptualization, Funding Acquisition, Resources, Supervision, Writing Review & Editing; Xian Xia: Conceptualization, Funding Acquisition, Resources, Supervision, Writing Review & Editing.

PubMed谷歌学术贡献李志良：概念化，方法论，软件，调查，形式分析，撰写原稿；高彪：概念化，资金获取，方法论，软件，调查，形式分析，撰写原稿；高秉思：数据策划，撰写原稿；李欣：概念化，资金获取，资源，监督，写作评论和编辑；冼霞：概念化，资金获取，资源，监督，写作评论和编辑。

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Reprints and permissionsAbout this articleCite this articleLi, X., Gao, B., Gao, B. et al. Transcriptome profiling reveals dysregulation of inflammatory and protein synthesis genes in PCOS.

转载和许可本文引用本文Li，X.，Gao，B.，Gao，B。等人。转录组分析揭示了PCOS中炎症和蛋白质合成基因的失调。

Sci Rep 14, 16596 (2024). https://doi.org/10.1038/s41598-024-67461-4Download citationReceived: 26 February 2024Accepted: 11 July 2024Published: 18 July 2024DOI: https://doi.org/10.1038/s41598-024-67461-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1416596（2024）。https://doi.org/10.1038/s41598-024-67461-4Download引文收到日期：2024年2月26日接受日期：2024年7月11日发布日期：2024年7月18日OI：https://doi.org/10.1038/s41598-024-67461-4Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsPCOSCo-DEGsGenomic analysis

关键词中远集团脱气基因组分析

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