YTHDF2 promotes spermagonial adhesion through modulating MMPs decay via m6A/mRNA pathway

Huang, Tao; Liu, Zidong; Zheng, Yi; Feng, Tongying; Gao, Qiang; Zeng, Wenxian

doi:10.1038/s41419-020-2235-4

Cited by 56 publications

(44 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the 311 genes that were downregulated in the 168 KO (Table S1), 72 are related to extracellular matrix (p<1.35e-06), which is crucial for oocyte 169 fertility. Interestingly, in sperm too, m 6 A regulation of metallopeptidase is mediated by Ythdf2 170 (Huang et al 2020). 171…”

mentioning

confidence: 99%

Context-dependent functional compensation between Ythdf m6A readers

Lasman

Krupalnik

Geula

et al. 2020

Preprint

View full text Add to dashboard Cite

15The N6-methyladenosine (m 6 A) modification is the most prevalent post-transcriptional mRNA 16 modification, regulating mRNA decay, translation and splicing. It plays a major role during normal 17 development, differentiation, and disease progression. The modification is dynamically regulated 18 by a set of writer, eraser and reader proteins. The YTH-domain family of proteins: Ythdf1, Ythdf2, 19and Ythdf3, are three homologous m 6 A binding proteins, which have different cellular functions. 20However, their sequence similarity and their tendency to bind the same targets suggest that they 21 may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer for each of 22 E7.5, and to embryonic lethality. By using systematic genotyping of viable offspring, we found 81 that in early development there is compensation between the readers, which is dosage-82 dependent, i.e. Ythdf2-hetrozygouse mice need to have at least one functional copy of another 83Ythdf reader to escape mortality. Furthermore, we used mESCs to analyze the function of each 84Ythdf reader separately, and together. We found that only triple-KO mESCs are not able to 85 differentiate properly, and present a prolonged mRNA degradation rate, similar to the effect 86shown in Mettl3-KO, while no significant effect is seen in the single-KOs. This suggests that just 87 like in early development, in mouse ESCs, a system in which all the readers are expressed in the 88 same cells and compartment, there is a redundancy between Ythdf readers, which enables 89 compensation in the absence of the other. 90 91Results 92 93Mettl3 writer plays an essential role in oogenesis and spermatogenesis 94 95We started by systematically testing the three readers in a specific system in-vivo, focusing on 96 spermatogenesis and oogenesis. m 6 A writers Mettl3 and Mettl14 and m 6 A erasers FTO and 97ALKBH5 were found to be essential for proper gametogenesis in mouse. Their KO typically leads 98to defective maturation of sperm or ova, and hypofertility (Xu et al.

show abstract

mentioning

confidence: 99%

Context-dependent functional compensation between Ythdf m6A readers

Lasman

Krupalnik

Geula

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…These reader proteins play a key role in regulating the mRNA metabolism. Previous report showed that YTHDF1 promotes translation by recognizing m6A, and YTHDF2 recognizes mRNA and often leads to mRNA degradation [13]. We found that FTO silencing could promote the appearance of the m6A peak in HOXB13 mRNA but was accompanied by a decrease in the mRNA expression of HOXB13.…”

Section: Fto Removes the M6a Modi Cation In The 3'utr Region Of Hoxb1mentioning

confidence: 47%

“…After YTHDF1 recognizes an m6A modi cation of mRNA, it can accelerate the translation process [12]. When YTHDF2 recognizes an m6A modi cation, it will promote the transportation of mRNA into the p-body, accelerate mRNA degradation, and inhibit protein translation [13]. It has been found that abnormal expression of these proteins exists in various tumors and affects the occurrence and progression of tumors [14].…”

Section: Introductionmentioning

confidence: 99%

FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway

et al. 2020

View full text Add to dashboard Cite

Background Abnormal FTO expression causes faulty m6A modi cations in mRNA and affects tumor progression. However, the expression and function of FTO in endometrial cancer (EC) and the genes regulated by FTO remain unclear. Methods qPCR detected the FTO expression level in EC tissues, and IHC staining determined the FTO protein expression in tissue arrays. FTO was stably overexpressed or knocked down in EC cell lines by lentiviruses. The biological roles of FTO in cancer cell metastasis and invasion were evaluated by woundhealing, Transwell assays and mouse intra-abdominal implantation models. mRNA-seq, RIP-seq, and MeRIP-seq were combined to comprehensively map the genes regulated by FTO. RNA pull-down, dualluciferase reporter and RNA stability experiments con rmed that YTHDF2 regulates the metabolism of HOXB13 mRNA via m6A. Western blot analysis con rmed that HOXB13 regulates EC cell metastasis and invasion through the WNT signaling pathway. Results FTO is more highly expressed in metastatic EC and can promote tumor metastasis and invasion in vivo and in vitro. By removing the m6A modi cation in the 3'UTR region of HOXB13, FTO abolishes m6A recognition by YTHDF2 and promotes the stability of HOXB13 mRNA and protein expression. High HOXB13 expression activates the WNT signaling pathway, promotes c-myc, snail, MMP2, MMP7, and MMP9 expression, and inhibits E-cadherin expression, leading to tumor metastasis and invasion. Conclusions FTO promotes HOXB13 expression through m6A, activates the WNT signaling pathway, and promotes EC invasion and metastasis. FTO is a new potential target for the treatment of tumor metastasis.

show abstract

“…The insulin-like growth factor 2 mRNA binding protein (IGF2BP) family proteins, including IGF2BP1-3, can recognize m 6 A containing transcripts. IGF2BPs exert their functions via recruiting RNA stabilizers (Huang H. et al, 2018). Eukaryotic initiation factor 3 (EIF3) can facilitate cap-independent translation (Meyer et al, 2015).…”

Section: Alkbh5mentioning

confidence: 99%

“…Moreover, YTHDF2 is also involved in the initation of other biological process. In spermatogenesis, YTHDF2 regulates cell proliferation and adhesion via modulating the m 6 A methylation of MMPs and simultaneously decreasing the overall translational output (Huang T. et al, 2020). Knockdown of YTHDF2 promotes the expression of MAP2K4 and MAP4K4 and activates MAPK and NF-κB signaling pathways, which facilitate the expression of proinflammatory cytokines and exacerbate the inflammatory response in LPS-stimulated RAW 264.7 cells (Yu et al, 2019).…”

Section: Ythdf2mentioning

confidence: 99%

The Potential Roles of RNA N6-Methyladenosine in Urological Tumors

Yang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

N6-methyladenosine (m 6 A) is regarded as the most abundant, prevalent and conserved internal mRNA modification in mammalian cells. M 6 A can be catalyzed by m 6 A methyltransferases METTL3, METTL14 and WTAP (writers), reverted by demethylases ALKBH5 and FTO (erasers), and recognized by m 6 A-binding proteins such as YTHDF1/2/3, IGF2BP1/2/3 and HNRNPA2B1 (readers). Emerging evidence suggests that m 6 A modification is significant for regulating many biological and cellular processes and participates in the pathological development of various diseases, including tumors. This article reviews recent studies on the biological function of m 6 A modification and the methylation modification of m 6 A in urological tumors.

show abstract

YTHDF2 promotes spermagonial adhesion through modulating MMPs decay via m6A/mRNA pathway

Cited by 56 publications

References 41 publications

Context-dependent functional compensation between Ythdf m6A readers

Context-dependent functional compensation between Ythdf m6A readers

FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway

The Potential Roles of RNA N6-Methyladenosine in Urological Tumors

Contact Info

Product

Resources

About