更新于：2024-09-19

YTHDC2

更新于：2024-09-19

基本信息

别名

3'-5' RNA helicase YTHDC2、DKFZp564A186、FLJ10053

+ [5]

简介

3'-5' RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells (PubMed:26318451, PubMed:29033321, PubMed:29970596). Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, a modification present at internal sites of mRNAs and some non-coding RNAs that plays a role in the efficiency of RNA processing and stability (PubMed:26318451, PubMed:29033321). Essential for ensuring a successful progression of the meiotic program in the germline by regulating the level of m6A-containing RNAs (By similarity). Acts by binding and promoting degradation of m6A-containing mRNAs: the 3'-5' RNA helicase activity is required for this process and RNA degradation may be mediated by XRN1 exoribonuclease (PubMed:29033321). Required for both spermatogenesis and oogenesis (By similarity).

关联

100 项与 YTHDC2 相关的临床结果

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100 项与 YTHDC2 相关的转化医学

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0 项与 YTHDC2 相关的专利（医药）

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227

项与 YTHDC2 相关的文献（医药）

2024-12-31·Epigenetics

m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage

Article

作者: Feng, Lei ; Li, Yanan ; Wang, Fang ; Wang, Jianhua ; Li, Fengfeng ; Jiang, Pei ; Meng, Junjun ; Wei, Shanshan ; Wang, Lei

Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.

2024-12-01·Molecular Genetics and Genomics

A homozygous missense variant in YTHDC2 induces azoospermia in two siblings

Article

作者: Zhang, Feng ; Satti, Humayoon Shafique ; Xiao, Jianqiu ; Khan, Tahir Naeem ; Faheem, Muhammad ; Liu, Chunyu ; Tian, Shixiong

Male infertility is a complex multifactorial reproductive disorder with highly heterogeneous phenotypic presentations. Azoospermia is a medically non-manageable cause of male infertility affecting ∼1% of men. Precise etiology of azoospermia is not known in approximately three-fourth of the cases. To explore the genetic basis of azoospermia, we performed whole exome sequencing in two non-obstructive azoospermia affected siblings from a consanguineous Pakistani family. Bioinformatic filtering and segregation analysis of whole exome sequencing data resulted in the identification of a rare homozygous missense variant (c.962G>C, p. Arg321Thr) in YTHDC2, segregating with disease in the family. Structural analysis of the missense variant identified in our study and two previously reported functionally characterized missense changes (p. Glu332Gln and p. His327Arg) in mice showed that all these three variants may affect Mg²⁺ binding ability and helicase activity of YTHDC2. Collectively, our genetic analyses and experimental observations revealed that missense variant of YTHDC2 can induce azoospermia in humans. These findings indicate the important role of YTHDC2 deficiency for azoospermia and will provide important guidance for genetic counseling of male infertility.

2024-12-01·Cellular and Molecular Life Sciences

METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism

Article

作者: Duan, Feifan ; Chen, Shuya ; Zhou, Lei ; Gao, Yu ; Zhang, Yukun ; Wang, Wenjing ; Sheng, Zhiyong ; Wang, Yaju ; Li, Qiang ; Meng, Xiangshu

AbstractPapillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.

项与 YTHDC2 相关的新闻（医药）

2024-01-07

·生物探索

Mol Cancer | 中山大学潘志忠/林俊忠/周驰发现促进结直肠癌肝转移的调控新机制

肝转移是结直肠癌(CRC)患者死亡的主要原因。新出现的证据表明，环状RNA (circRNA)在癌症进展中起着关键作用。然而，其在结直肠癌肝转移中的作用在很大程度上仍然未知。2023年12月13日，中山大学潘志忠、林俊忠及周驰共同通讯在Molecular Cancer（IF=37）在线发表题为“A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis”的研究论文，该研究证明，由m6 A修饰的环状RNA驱动的正反馈回路促进结直肠癌肝转移。Circ-YAP在伴有肝转移的结直肠癌中显著上调，与预后不良相关。Circ-YAP促进CRC细胞在体外的迁移和侵袭，并促进患者源性异种移植(PDX)模型体内的肝转移。从机制上讲，circ-YAP编码了一种含有220个氨基酸的新型截断蛋白，称为YAP-220aa，该蛋白与LATS1竞争性结合，导致YAP去磷酸化和核易位，从而激活一系列促进转移的基因。重要的是，N6-甲基腺苷(m6 A)修饰协调了circ-YAP翻译的有效起始，需要m6 A“读取器”YTHDF3和eIF4G2翻译起始复合物。有趣的是，circ-YAP被YAP/TEAD复合物转录增强，从而形成一个正调控前馈回路。总之，该研究揭示了circ-YAP编码的一个以前未被表征的癌蛋白，这意味着一个有希望的结直肠癌肝转移患者的生物标志物和治疗靶点。结直肠癌(Colorectal cancer, CRC)是消化道最常见的恶性肿瘤之一，其发病率和死亡率在所有恶性肿瘤中分别排名第三和第二位。肿瘤转移是结直肠癌患者死亡的主要原因。临床上约有45-60%的结直肠癌患者存在肝转移，90%以上的肝转移不能初步切除。未经手术治疗的结直肠癌肝转移患者中位生存时间仅为6.9个月，5年生存率不足5%。因此，破解结直肠癌肝转移机制，发现预防和干预转移的新治疗靶点，提高患者生存率具有重要的临床意义。环状RNA (Circular RNA, circRNA)是一类特殊的内源性RNA分子，具有共价闭环结构，没有传统的5′端“帽状结构”和3′端聚A尾部。一些circRNA被确定为预测疾病进展和预后的可用生物标志物。最近的一些证据表明circRNA能够被翻译成功能性肽。此外，circRNAs编码的截断蛋白如E-Cad-254aa和ARHGAP35-1289aa分别被报道在胶质瘤和肝细胞癌中发挥关键作用。由于从头到尾的形状，circRNA以帽独立的方式编码蛋白质，由内部核糖体进入位点(IRES)或m6 A修饰驱动。m6 A是真核RNA中最丰富的内部修饰，具有动态可逆性，由m6 A写入器(METTL3/14和WTAP)催化，由m6 A“擦除器”(FTO和ALKBH5)去除，由m6 A读取器(YTHDF1/2/3和ythdc2 /2)识别。迄今为止，只有少数这些隐藏在环状RNAs中的小内源性蛋白被表征，绝大多数的功能相关性尚未被发现。机理模式图（图源自Molecular Cancer ）该研究发现circRNA circ-YAP是CRC肝转移的驱动因素。Circ-YAP包含一个220-aa的开放阅读框(ORF)，并以m6 A依赖的方式编码一种新的YAP蛋白异构体，称为YAP-220aa。此外，还发现YAP220aa通过阻止LATS1介导的YAP磷酸化和细胞质保留来激活YAP信号。该研究揭示了circ-YAP编码的一个以前未被表征的癌蛋白，这意味着一个有希望的结直肠癌肝转移患者的生物标志物和治疗靶点。参考文献：Zeng K, Peng J, Xing Y, Zhang L, Zeng P, Li W, Zhang W, Pan Z, Zhou C, Lin J. A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis. Mol Cancer. 2023 Dec 13;22(1):202. doi: 10.1186/s12943-023-01848-1. PMID: 38087322; PMCID: PMC10717141.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

2023-02-08

·生物谷

Molecular Cancer: LncRNA ZNRD1-AS1通过miR-942/TNS1轴促进恶性肺细胞的增殖、迁移和血管生成

肺癌是癌症死亡率最高的疾病，是世界范围内一个重大的公共卫生问题。吸烟是肺癌的主要原因，流行病学研究也表明，患肺癌的风险与个人一生中吸烟的频率和持续时间有关。肺癌是癌症死亡率最高的疾病，是世界范围内一个重大的公共卫生问题。吸烟是肺癌的主要原因，流行病学研究也表明，患肺癌的风险与个人一生中吸烟的频率和持续时间有关。最近的一项使用单细胞体细胞突变分析的研究报告称，吸烟通过增加体细胞突变的比例而增加患肺癌的风险。然而，仍有许多肺癌患者不具有这些基因突变，或者因此而对具有这些突变基因的患者治疗效果甚微，其机制尚不清楚。图片来源: https://pubmed.ncbi.nlm.nih.gov/36638328/ 近日，来自苏州大学苏州医学院的研究者们在Molecular Cancer杂志上发表了题为“lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2”的文章，该研究揭示了ZNRD1-AS1在肺癌中发挥重要作用，具有临床意义。此外，研究结果表明，m6A修饰可能通过m6A阅读器YTHDC2介导ZNRD1-AS1/miR-942/TNS1轴的调节。肺癌是最常见的癌症形式，死亡率很高，使其成为全球公共卫生问题。N6-甲基腺苷(M6A)的修饰是一个高度动态和可逆的过程，涉及多种重要的生物学过程。本研究利用体外、体内和多组学生物信息学方法，研究长非编码(LNC)RNA锌带结构域1-反义1(ZNRD1-AS1)的功能及其调控机制。研究者用含YTHDC2结构域的2(YTHDC2)RNA免疫沉淀(RIP)测序鉴定与m6A‘Reader’结合的RNA。利用甲基化RIP-PCR/定量聚合酶链式反应、下拉试验和RNA稳定性试验，分析了m6A修饰和ZNRD1-AS1调控。应用生物信息学方法检测ZNRD1-AS1在肺癌组织中的表达水平及临床意义。利用荧光原位杂交和定量聚合酶链式反应技术，确定了ZNRD1-AS1的亚细胞定位。通过细胞迁移、增殖和血管生成实验，检测ZNRD1-AS1在肺癌中的生物学功能。此外，通过异种移植动物模型验证了ZNRD1-AS1的体内抑瘤作用。通过生物信息学分析和体外分析，还预测和验证了下游microRNAs(MiRs)和竞争内源RNAs。本研究提供证据表明，M6A修饰介导了YTHDC2介导的ZNRD1-AS1在肺癌和香烟烟雾暴露细胞中的下调。低水平的ZNRD1-AS1表达与不良的临床病理特征、免疫浸润和预后有关。ZNRD1-AS1过表达在体内外均能抑制肺癌细胞的增殖、迁移和血管生成，并抑制裸鼠体内肿瘤生长。用甲基化抑制剂3-Deazaadenosine或去甲基化抑制剂Meclofenamic处理细胞可以控制ZNRD1-AS1的表达。此外，miR-942/tensin 1(TNS1)轴是ZNRD1-AS1的下游调控信号通路。机制总结图图片来源: https://pubmed.ncbi.nlm.nih.gov/36638328/ 综上所述，本研究通过体内外实验和生物信息学分析，阐明了ZNRD1-AS1对肺癌细胞增殖和迁移的影响，并论证了其临床意义。此外，从表观基因组学角度进一步探讨了其上游调控机制，结果表明，它含有m6A修饰位点，并受m6A介导的“读者”蛋白YTHDC2的调控。更好地了解ZNRD1-AS1的m6A修饰将有助于更深入地了解肺癌的潜在分子机制，并有助于开发更有效的个性化治疗策略。（生物谷 Bioon.com）参考文献 Jin Wang et al. lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2. Mol Cancer. 2022 Dec 30;21(1):229. doi: 10.1186/s12943-022-01705-7.