REPRODUCTION
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2022
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IF 3.923
Luchun Zhang,Meng Yuan,Xingwei Huang,Qianzi Cao,Shaogang Huang,Ruizhen Sun,Lei Lei
In brief: Several factors affect the reprogramming efficiency of nuclear transfer embryos. This study shows that inhibiting 18S rRNA m6A methyltransferase METTL5 during nuclear transfer can improve the developmental rate of nuclear transfer embryos. Abstract: N6-methyladenosine (m6A) is one of the most important epigenetic modifications in eukaryotic RNAs, which regulates development and diseases. It is identified by several proteins. Methyltransferase-like 5 (METTL5), an enzyme that methylates 18S rRNA m6A, controls the translation of proteins and regulates pluripotency in embryonic stem cells. However, the functions of METTL5 in embryonic development have not been explored. Here, we found that Mettl5 was upregulated in somatic cell nuclear transfer (SCNT) embryos compared with normal fertilized embryos. Therefore, we hypothesized that METTL5 knockdown during the early stage of SCNT would improve the developmental rate of SCNT embryos. Notably, injection of Mettl5 siRNA (si-Mettl5) into enucleated oocytes during nuclear transfer increased the rate of development and the number of cells in blastocysts. Moreover, inhibition of METTL5 reduced the activity of phosphorylated ribosomal protein S6, decreased the levels of the repressive histone modification H3K27me3 and increased the expression of activating histone modifications H3K27ac and H3K4me3 and mRNA levels of some 2-cell-specific genes. These results expand our understanding of the role of METTL5 in early embryonic development and provide a novel idea for improving the efficiency of nuclear transfer cloning.
研究领域:
分子生物学
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生殖生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2025
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IF 12
Mengya Zhang,Xueguang Zhang,Chen Tan,Ting Jiang,Zheng Cao,Yufei Chen,Feng Qiao,Gelin Huang,Chaoye Ma,Huixia Li,Mei Ye,Lei Wang,Liandong Zuo,Jun Yu,Xiaofeng Li,Yunfang Zhang,Yue-Qiu Tan,Shuibin Lin,Wenming Xu,Hao Chen
Recent studies have highlighted RNA modifications as integral regulators of gene expression during spermatogenesis. Ribosomal RNAs (rRNAs) are the most abundant RNA in cells, while the function and clinical relevance of rRNA modifications in spermatogenesis remain poorly understood. Here, we identified 4 pathogenic heterozygous variants of METTL5 in 1,427 patients with male infertility characterized as oligoasthenoteratozoospermia (OAT). The pathogenic variants of METTL5 led to the significantly decreased expression level of METTL5. Null mutation of 18S rRNA methyltransferase Mettl5 led to male infertility attributed to OAT during spermiogenesis, presenting defects in both the sperm head and tail. Notwithstanding the absence of notable changes in global translation after Mettl5 loss, we observed a compromised translational efficiency of mRNAs encoding proteins crucial for spermiogenesis, including Gk2 , Akap4 , Fsip2 , Odf2 , and Pgk2 . Intriguingly, therapeutic interventions via intracytoplasmic sperm injection in OAT couples with these variants resulted in successful pregnancies. These insights not only identify METTL5-mediated 18S rRNA m 6 A modification as a novel genetic determinant for OAT but also offer a new target to the genetic counseling, clinical diagnosis, and potential treatment strategies for male infertility.
研究领域:
分子生物学
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遗传学
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生殖医学
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RNA修饰
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发育生物学
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产品关联
DOI
PubMed
高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 3
·338-364
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IF 16.2
Peng Xia,Hao Zhang,Haofeng Lu,Kequan Xu,Xiang Jiang,Yuke Jiang,Xiangdong Gongye,Zhang Chen,Jie Liu,Xi Chen,Weijie Ma,Zhonglin Zhang,Yufeng Yuan
Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ( ENO1 ), triosephosphate isomerase 1 ( TPI1 ), solute carrier family 2 member 1 ( SLC2A1 ), and pyruvate kinase M2 ( PKM2 ). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
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2020
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IF 8.109
Bowen Rong,Qian Zhang,Jinkai Wan,Shenghui Xing,Ruofei Dai,Yuan Li,Jiabin Cai,Jiaying Xie,Yang Song,Jiawei Chen,Lei Zhang,Guoquan Yan,Wen Zhang,Hai Gao,Jing-Dong J. Han,Qianhui Qu,Honghui Ma,Ye Tian,Fei Lan
Summary N6 methylation at adenosine 1832 (m 6 A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m 6 A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.
研究领域:
分子生物学
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癌症研究
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细胞生物学
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遗传学
✓ 已验证
DOI
PubMed
高影响因子
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