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Long Noncoding RNA SYISL Regulates Myogenesis by Interacting with Polycomb Repressive Complex 2

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Long noncoding RNA SYISL regulates myogenesis by interacting with polycomb repressive complex 2 Jian Jun Jina,b,c,1, Wei Lva,b,c,1, Pan Xiaa,b,c, Zai Yan Xua,b,c, An Dai Zhenga,b,c, Xiao Jing Wanga,b,c, Shan Shan Wanga,b,c, Rui Zenga,b,c, Hong Mei Luoa,b,c, Guo Liang Lid,e,f, and Bo Zuoa,b,c,g,2 aKey Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China; bKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China; cDepartment of Animal Breeding and Genetics, College of Animal Science and Technology, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China China; dNational Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China; eAgricultural Bioinformatics Key Laboratory of Hubei Province, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China; fDepartment of Big Data Science, College of Informatics, Huazhong Agricultural University, 430070 Wuhan, Hubei, People’s Republic of China; and gThe Cooperative Innovation Center for Sustainable Pig Production, 430070 Wuhan, People’s Republic of China Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT, and approved September 11, 2018 (received for review January 26, 2018) Although many long noncoding RNAs (lncRNAs) have been identified are defined as RNA molecules greater than 200 nt in length that in muscle, their physiological function and regulatory mechanisms have negligible protein-coding capacity; they play important remain largely unexplored. In this study, we systematically character- roles in the epigenetic regulation of numerous biological pro- ized the expression profiles of lncRNAs during C2C12 myoblast cesses, including X-chromosome inactivation (14), genome im- differentiation and identified an intronic lncRNA, SYISL (SYNPO2 in- printing (15, 16), alternative splicing (17), stem cell maintenance tron sense-overlapping lncRNA), that is highly expressed in muscle. and differentiation (18, 19), and human disease (20–22). During Functionally, SYISL promotes myoblast proliferation and fusion myogenesis, functional lncRNAs, such as SRA, Gtl2/Meg3, H19, but inhibits myogenic differentiation. SYISL knockout in mice re- linc-MD1, SINE-containing lncRNAs, Yam1, lncRNA-YY1, sults in significantly increased muscle fiber density and muscle LncMyoD, MALAT1, Dum, MUNC, Linc-RAM,andLnc-mg, mass. Mechanistically, SYISL recruits the enhancer of zeste homo- have been found to regulate muscle development and re- log 2 (EZH2) protein, the core component of polycomb repressive generation through diverse mechanisms (23–29). For example, the complex 2 (PRC2), to the promoters of the cell-cycle inhibitor skeletal muscle-specific overexpression of lnc-mg promotes muscle p21 MyoG gene and muscle-specific genes such as myogenin ( ), hypertrophy and increases muscle mass (29), and mutation in H19 MCK Myh4 muscle creatine kinase ( ), and myosin heavy chain 4 ( ), leads to significant muscle mass increase in mice (30). Compared leading to H3K27 trimethylation and epigenetic silencing of tar- with WT mice, Linc-RAM and MALAT1-KO mice display im- SYISL get genes. Taken together, our results reveal that is a re- paired and enhanced muscle regeneration, respectively (28, 31). pressor of muscle development and plays a vital role in PRC2- While numerous lncRNAs have been identified in muscle using mediated myogenesis. microarray, high-throughput sequencing, and single-nucleus RNA sequencing (snRNA-seq) analysis (32, 33), most of their roles in lncRNA | SYISL | PRC2 | H3K27 trimethylation | myogenesis myogenesis remain unclear, and many more lncRNAs have yet to be identified. yogenesis is a highly ordered process during which muscle To systematically identify the lncRNAs that are potentially Mstem cell proliferation, migration, differentiation, and fu- involved in myogenesis, we characterized the expression profiles sion are activated to form myofibers (1). This process is controlled of lncRNAs during C2C12 myoblast differentiation using micro- by a series of muscle-specific transcription factors, including myo- array analysis and identified 1,913 differentially expressed lncRNAs. genic differentiation 1 (MyoD), myogenin (MyoG), myogenic factor Based on these results, the lncRNA AK004418, located in the 5 (Myf5), muscle-specific regulatory factor 4 (MRF4, also known as fourth intron of the SYNPO2 gene, was identified and named “Myf6”), and myocyte enhancer factor 2 (MEF2) (2–4). In addition, epigenetic regulators, such as polycomb repressive complex 2 Significance (PRC2), YIN-YANG-1 (YY1), histone deacetylase complexes (HDACs), histone methyltransferase complexes (HMTs), DNA While numerous long noncoding RNAs (lncRNAs) have been methyltransferase complexes (DNMTs), the SWItch/Sucrose identified in muscle, most of their roles in myogenesis remain Non-Fermentable complex (SWI/SNF), and lysine methyl- unclear, and many more lncRNAs have yet to be identified. transferase 2A (KMT2A), also play crucial roles in muscle de- SYISL SYNPO2 – In this study, we identified an intronic lncRNA, ( velopment (2, 5 7). Previous studies have shown that myogenic intron sense-overlapping lncRNA), which is highly expressed in differentiation is associated with global chromatin landscape muscle and interacts directly with polycomb repressive complex changes, especially for the well-known repressive marker histone 2 (PRC2) to repress muscle development. The results reveal that H3 lysine 27 trimethylation (H3K27me3), which participates in SYISL acts as a regulatory RNA in PRC2-mediated myogenesis. the regulation of myogenic differentiation by silencing muscle- specific genes and cell-cycle genes (8, 9). Enhancer of zeste Author contributions: B.Z. designed research; J.J.J., W.L., P.X., A.D.Z., X.J.W., S.S.W., R.Z., homolog 2 (EZH2), the core component of PRC2, is capable of H.M.L., and B.Z. performed research; B.Z. contributed new reagents/analytic tools; J.J.J., H3K27me3 and is specifically required for early mouse muscle W.L., Z.Y.X., G.L.L., and B.Z. analyzed data; and J.J.J., W.L., and B.Z. wrote the paper. development (8, 10). Increased EZH2 expression inhibits skeletal The authors declare no conflict of interest. muscle cell differentiation by silencing muscle-specific genes (10, This article is a PNAS Direct Submission. 11), and EZH2 is associated with self-renewal of muscle satellite Published under the PNAS license. cells and muscle regeneration (12, 13). 1J.J.J. and W.L. contributed equally to this work. Genome-wide analysis of human and mouse genomes has 2To whom correspondence should be addressed. Email: [email protected]. revealed that noncoding RNAs (ncRNAs), including miRNAs, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. long noncoding RNAs (lncRNAs), Piwi-interacting RNAs, and 1073/pnas.1801471115/-/DCSupplemental. circular RNAs, are transcribed from most genomes. lncRNAs Published online October 2, 2018. E9802–E9811 | PNAS | vol. 115 | no. 42 www.pnas.org/cgi/doi/10.1073/pnas.1801471115 Downloaded by guest on September 29, 2021 “SYISL” (for “SYNPO2 intron sense-overlapping lncRNA”). The SYISL gene is highly expressed in skeletal muscle, and its expression increases with C2C12 cell differentiation. Gain- and loss-of-function analysis revealed that SYISL promotes myoblast proliferation and inhibits myogenic differentiation. Significantly, SYISL-KO mice have more muscle mass and greater muscle fiber density than WT mice. Mechanistically, SYISL acts as a regula- tory RNA that interacts directly with PRC2 to repress the ex- pression of target genes. Results lncRNA and mRNA Expression Profiles During C2C12 Myoblast Differentiation. To systematically identify lncRNAs involved in muscle cell differentiation, we used mRNA and lncRNA microarrays to identify differentially expressed lncRNAs during C2C12 cell differentiation (proliferating myoblasts and myo- blasts at 2, 5, and 8 d after cell differentiation, represented as “D0,”“D2,”“D5,” and “D8,” respectively). This microarray contained 13,868 lncRNA probes and 19,465 mRNA probes; an overview of the lncRNA and mRNA expression profiles is sum- marized in Dataset S1. In total, 5,684 lncRNAs and 9,069 mRNA probes with signals in at least 6 of 12 samples had flags in the Fig. 1. Characterization of the lncRNA SYISL gene. (A) Heatmap showing present or marginal categories (SI Appendix,Fig.S1A and B and the expression profiles of 356 up-regulated and 266 down-regulated Dataset S1). Among 5,684 lncRNA probes with signals, 4,205 lncRNAs during myogenic differentiation. (B) qPCR results showing that (73.98%) were annotated; intron sense-overlapping lncRNAs SYISL and MyHC were significantly up-regulated during myogenic differen- accounted for the largest proportion, followed by intergenic and tiation. MyHC is the myogenic differentiation marker gene. (C) qPCR results exon sense-overlapping lncRNAs (SI Appendix,Fig.S1C). The showing that SYISL was highly expressed in muscle tissues including the chromosomal distribution of lncRNAs was not uniform; most of longissimus dorsi, leg muscle, and tongue. (D) The distribution of SYISL in the the lncRNAs with signals were transcribed from chromosomes cytoplasm and nuclei of proliferating C2C12 cells
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