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更新于：2025-05-07

GEF-H1 x YTHDF1

更新于：2025-05-07

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项与 GEF-H1 x YTHDF1 相关的药物

US20250075210

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GEF-H1 x YTHDF1

作用机制-

在研机构

University Health Network

原研机构

University Health Network

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GEF-H1 x YTHDF1 相关的临床结果

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100 项与 GEF-H1 x YTHDF1 相关的转化医学

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0 项与 GEF-H1 x YTHDF1 相关的专利（医药）

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项与 GEF-H1 x YTHDF1 相关的文献（医药）

2022-04-01·Gastroenterology1区 · 医学

N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer

1区 · 医学

Article

作者: Rottapel, Robert ; Wong, Chi Chun ; Mo, Yulin ; Zhu, Lin ; Gao, Shanshan ; Cai, Zongwei ; Wu, Jianfeng ; Hezaveh, Kebria ; Wang, Lina ; Wang, Shiyan ; Bao, Yi ; Yu, Jun ; Zeng, Yong ; He, Housheng Hansen ; Kang, Wei ; Xu, Xin ; Chen, Huarong ; He, Aobo ; O'Brien, Catherine ; Su, Peiran ; Soares, Fraser ; Zheng, Gang ; Zhai, Jianning ; McGaha, Tracy ; Ci, Xinpei

BACKGROUND & AIMSN6-methyladenosine (m⁶A) governs the fate of RNAs through m⁶A readers. Colorectal cancer (CRC) exhibits aberrant m⁶A modifications and expression of m⁶A regulators. However, how m⁶A readers interpret oncogenic m⁶A methylome to promote malignant transformation remains to be illustrated.METHODSYTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m⁶A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m⁶A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP).RESULTSDNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m⁶A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo.CONCLUSIONSWe identify a novel oncogenic epitranscriptome axis of YTHDF1-m⁶A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.

2009-08-01·Journal of Genetics4区 · 生物学

RETRACTED ARTICLE: Dwarf mutations in grass pea (Lathyrus sativus L.): origin, morphology, inheritance and linkage studies

4区 · 生物学

Article

作者: Talukdar, Dibyendu

Induction of mutation has been used to create additional genetic variability in grass pea (Lathyrus sativus L.). During the ongoing investigations on different induced-morphological mutants, the author detected three types of dwarf mutants in grass pea. One mutant, designated as dwf1 type was earlier identified in colchicine-induced C2 generation of grass pea variety BioR-231 while the other two, designated as dwf2 and dwf3 were isolated in 250 Gy and 300 Gy gamma ray irradiated M2 progeny of variety 'BioR-231' and 'Hooghly Local', respectively. As compared to their parental varieties (controls), all the three mutants manifested stunted, erect and determinate stem, early maturity and tolerance to pod shattering habit. The mutants differed from each other, as well as with controls, in number of primary branches, nature of stipules and internodes, length of peduncle, leaflet and seed coat colour, seed yield and seed neurotoxin content. The three dwarf mutants were monogenically recessive and bred true in successive generations. F2 segregation pattern obtained from the crosses involving the three mutants indicated that dwarf mutation in grass pea was controlled by two independent non-allelic genes, assigned as df1 (for dwf1 type), df2 (for dwf2 type) and df3 (for dwf3 type), with the df1 locus being multiple allelic. Primary trisomic analyses revealed the presence of df1/df2 locus on the extra chromosome of trisomic type I, whereas df3 was located on the extra chromosome of type III. Linkage studies involving five other phenotypic markers suggested linked association of df1/df2 locus with lfc (leaflet colour) and wgn (winged internode) and df3 locus with cbl (seed coat colour). Both the loci; however, assorted independently with flower colour and stipule character. The dwarf types can be utilized as valuable tools for further cytogenetic research and breeding of grass pea.

Molecular Medicine

A novel mechanism of FTO modulating the progression of endometriosis through mediating the m6A methylation of GEF-H1 in a YTHDF1-dependent manner

Article

作者: Yang, Meng-Jie ; Huang, Zhi-Xiong ; Zhang, Hua-Ying ; Ding, Xin-Yu ; Zhou, Wei-Dong ; Sun, Qin-Kun ; Bai, Jian-Bin ; Lei, Yi-Hong ; Chen, Zheng-Yi ; Chen, Qiong-Hua ; Chen, Jia-Hao ; Lan, Jian-Fa ; Ren, Lu-Lu ; Lin, Dian-Chao

AbstractBackgroundEndometriosis (EMs) is a condition characterized by the growth of endometrial tissue outside the uterine cavity. Although this condition is benign, it has cancer-like features. N6-methyladenosine (m6A) is a common RNA modification involved in diverse biological processes, but its role in EMs remains unclear.MethodsA human endometrial stromal cell line (HESCs), primary eutopic endometrial stromal cells (Eu-ESCs), primary ectopic endometrial stromal cells (Ec-ESCs), and clinical samples were used in this study. A colorimetric assay was used to measure methylation levels in clinical and mouse EMs samples. Functional assays (CCK-8, EdU, Transwell, and wound healing) were used to evaluate phenotypic changes. m6A immunoprecipitation sequencing (MeRIP-seq) identified downstream targets. Mechanistic studies were conducted via qRT‒PCR, Western blot, RNA immunoprecipitation (RIP), dual-luciferase reporter, and RNA stability assays.ResultsWe detected aberrantly low levels of m6A within endometriotic lesions, which was attributed to increased expression of the m6A eraser fat mass and obesity-associated protein (FTO). Notably, estrogen and inflammatory factors, which are recognized as pathogenic agents in EMs amplify FTO expression while suppressing m6A levels. In vitro experiments demonstrated that overexpression of FTO in endometrial stromal cells leads to a reduction in m6A levels and concomitantly promotes their proliferation, migration, and invasion. Furthermore, both genetic deletion of Fto and chemical inhibition of FTO impeded the growth of ectopic endometrial lesions in vivo. By utilizing m6A-seq, we identified GEF-H1 (a Rho guanine nucleotide exchange factor) as a pivotal downstream target of FTO. Specifically, diminished m6A methylation at a certain site within the 3'UTR of GEF-H1 promotes its expression in a YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1)-dependent manner, thereby activating the RhoA pathway. Subsequent experiments revealed that GEF-H1 mediates the effects of FTO in promoting migration and invasion.ConclusionsThis study revealed that FTO decreases the m6A level of GEF-H1, thereby increasing its stability, which in turn activates the GEF-H1-RhoA pathway to promote the migration and invasion of endometrial stromal cells, thereby inducing EMs. Our findings suggest potential therapeutic avenues for targeting FTO to alleviate EMs progression.

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