MATR3

MATR3
  • 文章类型: Journal Article
    肝细胞癌(HCC)是全球癌症相关死亡率的主要原因之一。Matrin-3(MATR3)的致癌作用,一种核基质蛋白,在HCC中仍然未知。这里,我们基于综合生物信息学分析和功能研究记录了MATR3在HCC中的生物学功能。根据TCGA数据库,发现MATR3的表达与HCC的临床病理特征呈正相关。受试者工作特征(ROC)曲线和Kaplan-Meier(KM)曲线显示了MATR3在HCC患者中的诊断和预后潜力。分别。途径富集分析代表了MATR3在各种分子途径中的富集,包括细胞周期的调节。HCC细胞系中的功能测定显示,随着MATR3的稳定沉默,细胞增殖减少。同时,通过异种移植肿瘤实验验证了MATR3耗竭对HCC发展的抑制作用.此外,MATR3抑制还通过调节细胞周期相关基因的表达而导致细胞周期停滞。此外,联合免疫沉淀和质谱(Co-IP/MS)进一步证实了MATR3与HCC细胞中细胞周期调节因子的相互作用.此外,CIBERSORT和TIMER分析显示MATR3与HCC中的免疫浸润之间存在关联。总的来说,这项研究强调了MATR3在HCC中的新致癌功能,这可以全面解决细胞周期的异常变化如何促进肝癌的发展。MATR3可能作为HCC患者的预后预测因子和治疗靶点。
    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.
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  • 文章类型: Journal Article
    翼状胬肉是一种常见的眼表疾病,复发率高,发病机制尚不清楚。在目前的研究中,在6对人翼状胬肉和结膜组织中进行RNA测序,与对照组织相比,翼状胬肉中作为新候选基因的Matr3显著降低。此外,进行免疫沉淀以拉下MATR3,并且通过质谱鉴定WTAP与对照中的MATR3而不是翼状胬肉特异性相互作用。进行免疫沉淀以验证MATR3和WTAP/METTL3/METTL14复合物之间的相互作用。进行(甲基化)RNA免疫沉淀以进一步揭示WTAP和MATR3的结合亲和力在翼状胬肉中下调基因的RNA分子的3'UTR处丧失。总的来说,我们发现了MATR3和N6-甲基腺苷甲基转移酶复合物之间的交叉丢失,同时也表明了翼状胬肉对靶基因转录的潜在影响。
    Pterygium is a common eye surface disease with high recurrence and unclear pathogenesis. In current study, RNA sequencing was conducted in 6 pairs of human pterygium and conjunctival tissues, and Matr3 as a novel candidate gene was significantly reduced in pterygium compared to control tissues. Moreover, immunoprecipitation was performed to pull down MATR3, and WTAP specially interacting with MATR3 in control but not pterygium was identified by mass spectrum. Immunoprecipitation was performed to validate the interaction between MATR3 and WTAP/METTL3/METTL14 complex. (Methylated) RNA immunoprecipitation was performed to further reveal that the binding affinity of WTAP and MATR3 was lost at 3\' UTR of RNA molecules of down-regulated genes in pterygium. Overall, we figured out the loss of intercrossing between MATR3 and N6-methyladenosine methyltransferase complex, as well as indicated the potential impact on transcription of target genes in pterygium.
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  • 文章类型: Journal Article
    背景:三阴性乳腺癌(TNBC)是乳腺癌的一种亚型,具有较高的侵袭性和较差的预后。最近,长链非编码RNA(lncRNAs)已成为人类癌症进展的关键基因调节因子。然而,lncRNAs在TNBC中的功能和潜在机制尚不清楚.
    方法:基于公共数据库和生物信息学分析,检测到lncRNAMIDEAS-AS1在乳腺癌组织中的低表达,并在TNBC组织队列中进一步验证.MIDEAS-AS1对增殖的影响,迁移,通过体外和体内实验确定侵袭。进行RNA下拉测定和RNA免疫沉淀(RIP)测定以揭示MIDEAS-AS1和MATR3之间的相互作用。荧光素酶报告基因测定,染色质免疫沉淀(ChIP)和qRT-PCR用于评估MIDEAS-AS1/MATR3复合物对NCALD的调节作用。
    结果:LncRNAMIDEAS-AS1在TNBC中显著下调,这与TNBC患者的总生存期(OS)和无进展生存期(PFS)相关。MIDEAS-AS1过表达在体外和体内均显着抑制肿瘤的生长和转移。机械上,MIDEAS-AS1主要位于细胞核中,并与核蛋白MATR3相互作用。同时,NCALD被选为下游目标,受MIDEAS-AS1/MATR3复合物的转录调控,并进一步灭活NF-κB信号通路。此外,拯救实验表明,MIDEAS-AS1过表达引起的细胞恶性表型抑制可以通过抑制NCALD逆转。
    结论:总的来说,我们的结果表明,MIDEAS-AS1通过调节MATR3/NCALD轴在TNBC中充当肿瘤抑制因子,和MIDEAS-AS1可能作为TNBC的预后生物标志物。
    Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear.
    Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD.
    LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD.
    Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.
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  • 文章类型: Journal Article
    长散布的核元素(LINE)在塑造染色质状态中起着至关重要的作用,而与LINE合作的因素及其在高阶染色质组织中的作用仍然知之甚少。这里,我们发现MATR3是一种核基质蛋白,与反义LINE1(ASL1)RNA相互作用,通过相分离形成网状结构,为染色质空间组织提供动态平台。MATR3和ASL1RNAs互相影响核定位。MATR3耗尽后,染色质,特别是H3K27me3修饰的染色质,在细胞核中重新分布。高度转录MATR3相关ASL1RNA的拓扑关联域(TAD)在AML12和ES细胞中显示出降低的TAD内相互作用。MATR3耗尽增加了与MATR3相关的ASL1相邻的H3K27me3结构域的可及性,而不影响H3K27me3修饰。此外,肌萎缩侧索硬化症(ALS)相关的MATR3突变体改变了MATR3-ASL1RNA网的生物物理特征,并导致异常的H3K27me3染色。总的来说,我们揭示了MATR3和ASL1RNA在细胞核中聚集染色质中形成的网状结构的作用。
    Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.
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  • 文章类型: Journal Article
    噬血细胞性淋巴组织细胞增生症(HLH)是一种威胁生命的高炎症综合征,其特征是长时间发烧,血细胞减少,肝脾肿大,和吞噬作用。这是由于活化的巨噬细胞和自然杀伤细胞和/或细胞毒性T淋巴细胞的功能受损而发生的。NF-κB通路在炎症过度中起着至关重要的作用。Matrin3(MATR3)是一种核RNA/DNA结合蛋白,在基因表达调控中起着多种作用。我们招募了62例诊断为继发性HLH和吞噬作用的患者。收集来自25名患者和30名健康志愿者的外周血(PB)和来自47名患者的优质骨髓(BM)样品并用于分析。临床参数,包括年龄,性别,病因学,铁蛋白,纤维蛋白原,甘油三酯,和病毒感染状况,与生存预测无关。BM中NF-κB和MATR3mRNA表达下调的患者死亡率较高。与健康志愿者相比,患者PB中的MATR3mRNA表达较低。我们使用shRNA-MATR3-KD-THP1细胞来确定吞噬作用的功效。我们注意到shRNA-MATR3-KD-THP1细胞对坏死的JurkatE6细胞和羧酸酯修饰的聚苯乙烯乳胶珠具有更高的吞噬作用。在这里,我们提供了一种新的临床翻译标志物的证据,该标志物可作为继发性HLH的潜在治疗靶点.
    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis. This occurs as a result of activated macrophages and impaired function of natural killer cells and/or cytotoxic T lymphocytes. The NF-κB pathway plays a crucial role in hyperinflammation. Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays multiple roles in the regulation of gene expression. We enroll 62 patients diagnosed with secondary HLH and hemophagocytosis. Peripheral blood (PB) from 25 patients and 30 healthy volunteers and good quality bone marrow (BM) samples from 47 patients are collected and used for analysis. Clinical parameters, including age, sex, etiology, ferritin, fibrinogen, triglyceride, and viral infection status, had no association with survival prediction. Patients with downregulation of NF-κB and MATR3mRNA expression in the BM had a higher mortality rate. MATR3mRNA expression in PB was lower in patients compared to that in healthy volunteers. We use shRNA-MATR3-KD-THP1 cells to determine the efficacy of phagocytosis. We note that shRNA-MATR3-KD-THP1 cells had a higher phagocytic effect on necrotic Jurkat E6 cells and carboxylate modified polystyrene latex beads. Herein, we provide evidence of a new marker for clinical translation that can serve as a potential treatment target for secondary HLH.
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  • 文章类型: Journal Article
    The PDCD1 gene encodes PD-1, an important immune checkpoint protein and key immunotherapy target to treat cancer. PDCD1 is alternatively spliced to generate an exon 3-skipped isoform PD-1Δ3 that has been suggested to play an antagonistic role to PD-1, but the mechanism underlying alternative splicing of PDCD1 has never been explored. Here using a minigene system, we analysed the splicing pattern of PDCD1 in multiple cell lines and confirmed exon 3 skipping as the main alternative splicing event. Using deletion analysis of exon 3, we mapped two splicing enhancers in the exon: ESE3a and ESE3b. Using mutagenesis, RNA-affinity chromatography, mass spectrometry as well as depletion and overexpression of MATR3, we defined MATR3 as a splicing activator during PDCD1 exon 3 splicing that operates through binding to ESE3b. MATR3\'s splicing-stimulatory activity is counteracted by an RNA secondary structure around ESE3b and an RNA helicase DDX5. Furthermore, we identified ASOs that efficiently promotes PDCD1 exon 3 skipping in both minigene and endogenous-gene contexts. Our data support further study of the ASOs as potential drug candidates to treat cancer.
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