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Long Noncoding RNA LYPLAL1-AS1 Regulates Adipogenic Differentiation

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Long Noncoding RNA LYPLAL1-AS1 Regulates Adipogenic Differentiation Yang et al. Cell Death Discovery (2021) 7:105 https://doi.org/10.1038/s41420-021-00500-5 Cell Death Discovery ARTICLE Open Access Long noncoding RNA LYPLAL1-AS1 regulates adipogenic differentiation of human mesenchymal stem cells by targeting desmoplakin and inhibiting the Wnt/β-catenin pathway Yanlei Yang1,2,JunfenFan1,HaoyingXu1,LinyuanFan1,LuchanDeng1,JingLi 1,DiLi1, Hongling Li1, Fengchun Zhang2 and Robert Chunhua Zhao1 Abstract Long noncoding RNAs are crucial factors for modulating adipogenic differentiation, but only a few have been identified in humans. In the current study, we identified a previously unknown human long noncoding RNA, LYPLAL1- antisense RNA1 (LYPLAL1-AS1), which was dramatically upregulated during the adipogenic differentiation of human adipose-derived mesenchymal stem cells (hAMSCs). Based on 5′ and 3′ rapid amplification of cDNA ends assays, full- length LYPLAL1-AS1 was 523 nt. Knockdown of LYPLAL1-AS1 decreased the adipogenic differentiation of hAMSCs, whereas overexpression of LYPLAL1-AS1 enhanced this process. Desmoplakin (DSP) was identified as a direct target of LYPLAL1-AS1. Knockdown of DSP enhanced adipogenic differentiation and rescued the LYPLAL1-AS1 depletion- induced defect in adipogenic differentiation of hAMSCs. Further experiments showed that LYPLAL1-AS1 modulated DSP protein stability possibly via proteasome degradation, and the Wnt/β-catenin pathway was inhibited during 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; adipogenic differentiation regulated by the LYPLAL1-AS1/DSP complex. Together, our work provides a new mechanism by which long noncoding RNA regulates adipogenic differentiation of human MSCs and suggests that LYPLAL1-AS1 may serve as a novel therapeutic target for preventing and combating diseases related to abnormal adipogenesis, such as obesity. Introduction cells (MSCs) are multipotent stem cells and are considered Abnormal adipogenic differentiation is closely related to to be the main source of adipocytes1. Many studies have obesity, although the regulatory mechanisms involved demonstrated their potential use in treating obesity and – remain to be completely elucidated. Mesenchymal stem obesity-related diseases2 4.Therefore,elucidatingthereg- ulatory mechanism of adipogenesis in MSCs is of great importance for developing novel targets and therapies for Correspondence: Hongling Li ([email protected])or treating abnormal adipogenic-related diseases. Adipogen- Fengchun Zhang ([email protected]) or Robert esis from MSCs is mediated by a series of complex Chunhua Zhao ([email protected]) 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, processes, including the commitment of MSCs to pre- School of Basic Medicine Peking Union Medical College, Peking Union Medical adipocytes that then differentiate into mature adipocytes1. College Hospital, Center of Excellence in Tissue Engineering Chinese Academy The mechanism regulating this process involves the Wnt/ of Medical Sciences, Beijing Key Laboratory (No. BZO381), 100005 Beijing, China β-catenin pathway, Hedgehog pathway, transforming 2Department of Rheumatology and Clinical Immunology, Peking Union growth factor-β superfamily, and insulin-like growth factor Medical College Hospital, Clinical Immunology Center, Chinese Academy of signaling pathways as key mediators1. Many transcription Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, 100005 Beijing, China factors such as peroxisome proliferator-activated receptor-γ Edited by I. Amelio © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Yang et al. Cell Death Discovery (2021) 7:105 Page 2 of 16 (PPARγ) and members of the CCAAT/enhancer-binding downstream of LYPLAL1 on chromosome 1 and is tran- proteins (C/EBPs) also regulate this process5. However, the scribed from the opposite direction relative to LYPLAL1. full scope of transcription factors and pathways involved in This lncRNA was dramatically upregulated during adipo- MSC adipogenesis remains to be well defined. genic differentiation of hAMSCs (Fig. 1a, b and Fig. S1d, e), Long noncoding RNAs (LncRNAs) represent a sub- which was also confirmed by a real-time quantitative reverse family of transcripts that are >200 nt and have limited transcription-PCR (qRT-PCR) assay (Fig. 1d). 5′ and 3′ protein-encoding potential6,7. They have pivotal roles in Rapid amplification of cDNA ends (RACE) assays identified various biological processes, such as X chromosome that the full length of LYPLAL1-AS1 was 523 nt (Fig. 1cand – inactivation8, chromatin remodeling9 11, transcriptional Fig. S1f). repression12, cancer metastasis13, and stem cell fate The specific subcellular location of lncRNAs is essential – determination14 18. For example, lncRNA PGC1β-OT1 for understanding their functions and mechanisms. Cell reciprocally regulates mouse MSC adipogenic and osteo- fractionation followed by qRT-PCR demonstrated that genic differentiation through antagonizing miR-148a-3p LYPLAL1-AS1 displayed mainly a cytoplasmic distribution and enhancing the KDM6B effect19. LncRNA GAS5 serves (>70%) (Fig. 1e). As controls, glyceraldehyde 3-phosphate as a sponge for miR-18a to inhibit the adipogenic differ- dehydrogenase (GAPDH) displayed a cytoplasmic dis- entiation of human MSCs20. LncRNA ADINR regulates tribution, whereas U1 displayed a nuclear distribution adipogenesis of human MSCs by directly binding to PA1 (Fig. 1e). The RNA fluorescent in situ hybridization (FISH) and then modulates histone modification of the C/EBPα assay further validated that LYPLAL1-AS1 was distributed locus, thereby activating the transcription of C/EBPα21.To mainly in the cytoplasm. 18S rRNA and U6 were used as date, only a few lncRNAs have been identified that regulate controls (Fig. 1f). the adipogenic differentiation of human MSCs. Several lncRNAs have been reported to regulate adipogenic dif- LYPLAL1-AS1 depletion inhibits adipogenic differentiation – ferentiation, lipid metabolism, and obesity22 24, and given of hAMSCs, whereas its overexpression promotes this their tissue-specific expression patterns, lncRNAs can process serve as biomarkers for obesity25. To evaluate the effect of LYPLAL1-AS1 on adipogenic In the current study, we identified a previously differentiation, we silenced LYPLAL1-AS1 in hAMSCs unknown human lncRNA, LYPLAL1-antisense RNA1 using two pairs of specific short interfering RNAs (siR- (LYPLAL1-AS1), and showed that it has a role in adipo- NAs) (Fig. 2a). Then, hAMSCs were induced to differ- genic differentiation. Our findings provide new insights entiate into adipocytes. qRT-PCR and western blot into understanding the mechanism of adipogenic differ- analyses showed that LYPLAL1-AS1 knockdown resulted entiation of hAMSCs and suggest that LYPLAL1-AS1 in notably decreased expression of adipogenic markers may serve as a novel therapeutic target for adipogenesis- PPARγ, AP2, LPL, and CEBPα at both messenger RNA related disorders. (mRNA) and protein levels, as compared with cells transfected with the control siRNA (Fig. 2b, c). Lipid Results droplets in adipocytes are visualized with the reagent oil Identification, validation, and characterization of LYPLAL1- red O, which can be used to determine the efficiency of AS1 during the adipogenic differentiation of hAMSCs adipogenic differentiation27. Consistently, knockdown of hAMSCs isolated from human adipose tissue are fibro- LYPLAL1-AS1 decreased the adipogenic differentiation blast-like, plastic-adherent cells that have the potential to efficiency of hAMSCs (Fig. 2d, e). To exclude any off- differentiate into adipocytes and osteocytes; they are positive target effects of the siRNAs used for LYPLAL1-AS1 for CD29, CD73, CD44, CD90, and CD105 expression and knockdown, we performed further knockdown assays are negative for CD206, CD34, HLA-DR, CD45, and CD106 using RNase-H-based antisense oligonucleotides (ASOs). expression (Fig. S1a–c)26. To systematically identify func- Likewise, ASO targeting of LYPLAL1-AS1 not only tional lncRNAs that are involved in the regulation of downregulated the levels of adipogenic markers PPARγ, hAMSC adipogenic differentiation, we performed micro- AP2, and LPL (Fig. S2a–c) but also decreased the adipo- arrayanalysisbeforeandafteradipogenic differentiation of genic differentiation efficiency of hAMSCs (Fig. S2d, e). hAMSCs from three donors. Next, lncRNA expression To further confirm the function of LYPLAL1-AS1 in adi- profiles were analyzed according to stringent criteria (fold pogenicdifferentiationofhAMSCs,westablyoverexpressed change ≥ 2, expression value ≥ 3, and P <0.05).Weidentified full-length LYPLAL1-AS1 using lentivirus
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