Dataset Information

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

ABSTRACT:

Background

As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown.

Results

We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells.

Conclusions

Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function.

SUBMITTER: Yang Y

PROVIDER: S-EPMC9195452 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

Yang Yeming Y Shuai Ping P Li Xiao X Sun Kuanxiang K Jiang Xiaoyan X Liu Wenjing W Le Weidong W Jiang Haisong H Liu Yuping Y Zhu Xianjun X

BMC biology 20220613 1

<h4>Background</h4>As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown.<h4>Results</h4>We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in r ...[more]

PMID: 35698136

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Project description:Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3' untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies. KEY POINTS: ZFP14 under-expression is associated with ccRCC tumourigenesis and progression. METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC. ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.

Dataset Information

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

Background

Results

Conclusions

Publications

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

Similar Datasets

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