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      mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis

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          Abstract

          The pathogenesis of acute kidney injury (AKI) is still not fully understood, and effective interventions are lacking. Here, we explored whether methyltransferase 3 (METTL3) was involved in the progression of AKI via regulation of cell death. We reported that PT（proximal tubule）-METTL3-knockout (KO) noticeably suppressed ischemic-induced AKI via inhibition of renal cell apoptosis. Furthermore, we also found that the expression of mmu-long non-coding RNA (lncRNA) 121686 was upregulated in antimycin-treated Boston University mouse proximal tubule (BUMPT) cells and a mouse ischemia-reperfusion (I/R)-induced AKI model. Functionally, mmu-lncRNA 121686 could promote I/R-induced mouse renal cell apoptosis. Mechanistically, mmu-lncRNA 121686 acted as a competing endogenous RNA (ceRNA) to prevent microRNA miR-328-5p-mediated downregulation of high-temperature requirement factor A 3 (Htra3). PT-mmu-lncRNA 121686-KO mice significantly ameliorated the ischemic-induced AKI via the miR-328-5p/HtrA3 axis. In addition, hsa-lncRNA 520657, homologous with lncRNA 121686, sponged miR-328-5p and upregulated Htra3 to promote I/R-induced human renal cell apoptosis. Interestingly, we found that mmu-lncRNA 121686/hsa-lncRNA 520657 upregulation were dependent on METTL3 via N 6-methyladenosine (m 6A) modification. The mmu-lncRNA 121686/miR-328-5p or hsa-lncRNA 520657/miR-328-5p /HtrA3 axis was induced in vitro by METTL3 overexpression; in contrast, this effect was attenuated by METTL3 small interfering RNA (siRNA). Furthermore, we found that PT-METTL3-KO or METTL3 siRNA significantly suppressed ischemic, septic, and vancomycin-induced AKI via downregulation of the mmu-lncRNA 121686/miR-328-5p/HtrA3 axis. Taken together, our data indicate that the METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 axis potentially acts as a therapeutic target for AKI.

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          Abstract

          Zhang et al. revealed that the METTL3/mmu-lncRNA 121686 or hsa-lncRNA 520657/miR-328-5p/HtrA3 axis is responsible for the progression of I/R-, CLP-, and VAN-induced AKI. Moreover, METTL3 siRNA is potential therapy way for the AKI.

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          Functional Classification and Experimental Dissection of Long Noncoding RNAs

          Florian Kopp, Joshua Mendell (2018)
          Over the last decade, it has been increasingly demonstrated that the genomes of many species are pervasively transcribed, resulting in the production of numerous long noncoding RNAs (lncRNAs). At the same time, it is now appreciated that many types of DNA regulatory elements, such as enhancers and promoters, regularly initiate bidirectional transcription. Thus, discerning functional noncoding transcripts from a vast transcriptome is a paramount priority, and challenge, for the lncRNA field. In this review, we aim to provide a conceptual and experimental framework for classifying and elucidating lncRNA function. We categorize lncRNA loci into those that regulate gene expression in cis versus those that perform functions in trans , and propose an experimental approach to dissect lncRNA activity based on these classifications. These strategies to further understand lncRNAs promise to reveal new and unanticipated biology, with great potential to advance our understanding of normal physiology and disease.
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            Endogenous microRNA sponges: evidence and controversy.

            Daniel Thomson, Marcel E Dinger (2016)
            The competitive endogenous RNA (ceRNA) hypothesis proposes that transcripts with shared microRNA (miRNA) binding sites compete for post-transcriptional control. This hypothesis has gained substantial attention as a unifying function for long non-coding RNAs, pseudogene transcripts and circular RNAs, as well as an alternative function for messenger RNAs. Empirical evidence supporting the hypothesis is accumulating but not without attracting scepticism. Recent studies that model transcriptome-wide binding-site abundance suggest that physiological changes in expression of most individual transcripts will not compromise miRNA activity. In this Review, we critically evaluate the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions.
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              Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers

              Hailing Shi, Jiangbo Wei, Chuan Sheng He (2019)
              Cellular RNAs are naturally decorated with a variety of chemical modifications. The structural diversity of the modified nucleosides provides regulatory potential to sort groups of RNAs for organized metabolism and functions, thus affecting gene expression. Recent years have witnessed a burst of interest in and understanding of RNA modification biology, thanks to the emerging transcriptome-wide sequencing methods for mapping modified sites, highly-sensitive mass spectrometry for precise modification detection and quantification, and extensive characterization of the modification “effectors”, including enzymes (“writers” and “erasers”) that alter the modification level and binding proteins (“readers”) that recognize the chemical marks. However, challenges remain due to the vast heterogeneity in expression abundance of different RNA species, further complicated by divergent cell-type-specific and tissue-specific expression and localization of the effectors as well as modifications. In this review, we highlight recent progress in understanding the function of N 6 -methyladenosine (m 6 A), the most abundant internal mark on eukaryotic messenger RNA (mRNA), in light of the specific biological contexts of m 6 A effectors. We emphasize the importance of context for RNA modification regulation and function. RNA N 6 -methyladenosine (m 6 A) has emerged as a multifaceted controller for gene expression regulation, mediated through its effector proteins—writers, readers, and erasers. Shi et al . review recent advances in the mechanistic understandings of m 6 A effectors in various biological systems and cellular responses, emphasizing cellular and molecular contexts as important determinants of RNA modification functions.
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                Author and article information

                Contributors
                Dongshan Zhang
                Journal
                Journal ID (nlm-ta): Mol Ther
                Journal ID (iso-abbrev): Mol Ther
                Title: Molecular Therapy
                Publisher: American Society of Gene & Cell Therapy
                ISSN (Print): 1525-0016
                ISSN (Electronic): 1525-0024
                Publication date (Print): 07 December 2022
                Publication date (Electronic): 21 July 2022
                Volume: 30
                Issue: 12
                Pages: 3694-3713
                Affiliations
                [1 ]Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China
                [2 ]Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China
                [3 ]Department of Ophthalmology, Second Xiangya Hospital, Changsha, Hunan 410011, People’s Republic of China
                [4 ]Department of Nephrology, Second Xiangya Hospital, Changsha, Hunan 410011, People’s Republic of China
                [5 ]Department of Urinary Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People’s Republic of China
                [6 ]Department of Chest Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People’s Republic of China
                [7 ]Department of General Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People’s Republic of China
                [8 ]Hunan Clinical Medical Research Center for Acute Organ Injury and Repair, Changsha, Hunan 410011, People’s Republic of China
                Author notes
                [∗ ]Corresponding author: Dongshan Zhang, Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China. dongshanzhang@ 123456csu.edu.cn
                Article
                Publisher Item ID: S1525-0016(22)00435-X
                DOI: 10.1016/j.ymthe.2022.07.014
                PMC ID: 9734029
                PubMed ID: 35869629
                SO-VID: 2cddcd1b-dffa-4c53-b939-0f75ecdada03
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 26 March 2022
                Date accepted : 18 July 2022
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Molecular medicine
                Keywords: mmu_lncrna 121686,hsa_lncrna 520657,mettl3,mir-328-5phtra3,aki
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: mmu_lncrna 121686, hsa_lncrna 520657, mettl3, mir-328-5phtra3, aki

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