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Sense-overlapping lncRNA as a decoy of translational repressor protein for dimorphic gene expression.

ABSTRACT: Long noncoding RNAs (lncRNAs) are vastly transcribed and extensively studied but lncRNAs overlapping with the sense orientation of mRNA have been poorly studied. We analyzed the lncRNA DAPALR overlapping with the 5´ UTR of the Doublesex1 (Dsx1), the male determining gene in Daphnia magna. By affinity purification, we identified an RNA binding protein, Shep as a DAPALR binding protein. Shep also binds to Dsx1 5´ UTR by recognizing the overlapping sequence and suppresses translation of the mRNA. In vitro and in vivo analyses indicated that DAPALR increased Dsx1 translation efficiency by sequestration of Shep. This regulation was impaired when the Shep binding site in DAPALR was deleted. These results suggest that Shep suppresses the unintentional translation of Dsx1 by setting a threshold; and when the sense lncRNA DAPALR is expressed, DAPALR cancels the suppression caused by Shep. This mechanism may be important to show dimorphic gene expressions such as sex determination and it may account for the binary expression in various developmental processes.

SUBMITTER: Perez CAG

PROVIDER: S-EPMC8351930 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Sense-overlapping lncRNA as a decoy of translational repressor protein for dimorphic gene expression.

Perez Christelle Alexa Garcia CAG Adachi Shungo S Nong Quang Dang QD Adhitama Nikko N Matsuura Tomoaki T Natsume Toru T Wada Tadashi T Kato Yasuhiko Y Watanabe Hajime H

PLoS genetics 20210728 7

Long noncoding RNAs (lncRNAs) are vastly transcribed and extensively studied but lncRNAs overlapping with the sense orientation of mRNA have been poorly studied. We analyzed the lncRNA DAPALR overlapping with the 5´ UTR of the Doublesex1 (Dsx1), the male determining gene in Daphnia magna. By affinity purification, we identified an RNA binding protein, Shep as a DAPALR binding protein. Shep also binds to Dsx1 5´ UTR by recognizing the overlapping sequence and suppresses translation of the mRNA. I ...[more]

PMID: 34319983

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Project description:BackgroundDissection of the regulatory pathways that control skeletal muscle development and atrophy is important for the treatment of muscle wasting. Long noncoding RNA (lncRNA) play important roles in various stages of muscle development. We previously reported that Synaptopodin-2 (SYNPO2) intron sense-overlapping lncRNA (SYISL) regulates myogenesis through an interaction with enhancer of zeste homologue 2 (EZH2). However, it remains unclear whether SYISL homologues exist in humans and pigs, and whether the functions and mechanisms of these homologues are conserved among species.MethodsBioinformatics, cell fractionation, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used for the identification and molecular characterization of SYISL homologues in humans and pigs. Effects on myogenesis and muscle atrophy were determined via loss-of-function or gain-of-function experiments using C2C12 myoblasts, myogenic progenitor cells, dexamethasone (DEX), and aging-induced muscle atrophy models. RNA pulldown, RNA immunoprecipitation, dual luciferase reporting, and co-transfection experiments were used to explore the mechanisms of SYISL interactions with proteins and miRNAs.ResultsWe identified SYISL homologues in humans (designated hSYISL) and pigs (designated pSYISL). Functional experiments demonstrated that hSYISL and pSYISL regulate myogenesis through interactions with EZH2. Interestingly, we showed that SYISL functions to regulate muscle atrophy and sarcopenia through comparative analysis. SYISL is significantly up-regulated after muscle atrophy (P < 0.01); it significantly promotes muscle atrophy in DEX-induced muscle atrophy models (P < 0.01). SYISL knockdown or knockout alleviates muscle atrophy and sarcopenia in DEX-induced and aged mice. The tibialis anterior (TA) muscle weight of 3-month-old wild-type (WT) mice decreased by 33.24% after DEX treatment (P < 0.001), while the muscle weight loss of 3-month-old SYISL knockout mice was only 18.20% after DEX treatment (P < 0.001). SYISL knockout in 18-month-old WT mice significantly increased the weights of quadriceps (Qu), gastrocnemius (Gas), and TA muscles by 10.45% (P < 0.05), 13.95% (P < 0.01), and 24.82% (P < 0.05), respectively. Mechanistically, SYISL increases the expression levels of the muscle atrophy genes forkhead box protein O3a (FoxO3a), muscle ring finger 1 (MuRF1), and muscle atrophy-related F-box (Atrogin-1) via sponging of miR-23a-3p/miR-103-3p/miR-205-5p and thus promotes muscle atrophy. Additionally, we verified that human SYISL overexpression in muscles of 18-month-old WT mice significantly decreased the weights of Gas, Qu, and TA muscles by 7.76% (P < 0.01), 12.26% (P < 0.05), and 13.44% (P < 0.01), respectively, and accelerates muscle atrophy through conserved mechanisms.ConclusionsOur results identify SYISL as a conserved lncRNA that modulates myogenesis in mice, pigs, and humans. We also demonstrated its previously unknown ability to promote muscle atrophy.

Project description:Antisense lncRNAs were endogenous productions from the antisense strand of coding genes and were transcribed in the reverse direction of the sense gene. The purpose of this study was to evaluate the roles and functions of antisense lncRNAs in esophageal squamous cell carcinoma (ESCC). Differentially expressed antisense lncRNAs were initially screened based on transcriptome data of 119 paired ESCC samples in GSE53624 and were further validated in 6 paired ESCC samples from our institution. Log-rank test was adopted to identify ESCC prognosis-associated lncRNAs. Finally, functional assays were performed to reveal the functions of our identified antisense lncRNAs. In total, 174 antisense lncRNAs were differentially expressed in both GSE53624 and JSPH databases. Five of them were significantly associated with ESCC prognosis (NNT-AS1, NKILA, CCDC18-AS1, SLCO4A1-AS1, and AC110619.1). Of note, NNT-AS1 showed the most significant association with ESCC prognosis. The upregulation of NNT-AS1 was further confirmed in ESCC cells. Knockdown of NNT-AS1 inhibited ESCC cell proliferation, migration, promoted ESCC cells apoptosis, and induced cell cycle arrest in the G2/M stage. NNT-AS1 expression significantly correlated with its sense gene NNT. As expected, NNT-AS1 knockdown suppressed NNT expression. Inhibition of NNT repressed ESCC cell proliferation and migration, and accelerated ESCC cell apoptosis. Overexpression of NNT could rescue the suppressed proliferation and migration of ESCC cells induced by the silencing of NNT-AS1. In terms of mechanism, NNT-AS1 served as a competing endogenous RNA to sponge the miR-382-5p, which could inhibit NNT expression. Pathway enrichment analysis and western blot assay indicated that NNT-AS1 and NNT could regulate the cell cycle pathway. In conclusion, antisense lncRNA NNT-AS1 facilitated ECSS progression by targeting its sense gene NNT through sponging miR-382-5p. This study provided us with a deeper insight into the roles of antisense lncRNAs in ESCC and identified novel potential therapeutic targets.

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Sense-overlapping lncRNA as a decoy of translational repressor protein for dimorphic gene expression.

Publications

Sense-overlapping lncRNA as a decoy of translational repressor protein for dimorphic gene expression.

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