Epigenetic regulation of Wnt7b expression by the cis-acting long noncoding RNA Lnc-Rewind in muscle stem cells
- La Sapienza University of Rome, Italy
- La Sapienza University of Rome, National Research Council (CNR), Italy
- Sapienza University of Rome, Italy
- Istituto Italiano di Tecnologia, Italy
- La Sapienza, University of Rome, Italy
- National Research Council (CNR) at Sapienza University of Rome, Italy
Abstract
Skeletal muscle possesses an outstanding capacity to regenerate upon injury due to the adult muscle stem cells (MuSCs) activity. This ability requires the proper balance between MuSCs expansion and differentiation which is critical for muscle homeostasis and contributes, if deregulated, to muscle diseases. Here, we functionally characterize a novel chromatin-associated lncRNA, Lnc-Rewind, which is expressed in murine MuSCs and conserved in human. We find that, in mouse, Lnc-Rewind acts as an epigenetic regulator of MuSCs proliferation and expansion by influencing the expression of skeletal muscle genes and several components of the WNT (Wingless-INT) signalling pathway. Among them, we identified the nearby Wnt7b gene as a direct Lnc-Rewind target. We show that Lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates the in cis repression of Wnt7b by H3K9me2 deposition. Overall, these findings provide novel insights into the epigenetic regulation of adult muscle stem cells fate by lncRNAs.
Data availability
Sequencing data have been deposited in GEO under accession code GSE141396. All data generated or analysed during this study are included in the manuscript and supporting files
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Discovery of Novel LncRNA species differentially expressed during murine muscle differentiationEuropean Nucleotide Archive (ENA) accession number, PRJEB6112.
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Gene expression profiling of human and murine in vitro muscle differentiationGene Expression Omnibus (GEO) accession number, GSE70389.
Article and author information
Author details
Funding
Sapienza Università di Roma (prot. RM11715C7C8176C1)
- Monica Ballarino
Sapienza Università di Roma (RM11916B7A39DCE5)
- Monica Ballarino
Ministero dell'Istruzione, dell'Università e della Ricerca (RBSI14QMG0)
- Chiara Mozzetta
Associazione Italiana per la Ricerca sul Cancro (MyFIRST grant n.18993)
- Chiara Mozzetta
AFM-Telethon (#22489)
- Chiara Mozzetta
Collection of National Chemical Compounds and Screening Center (LIFE2020-Regione Lazio)
- Chiara Mozzetta
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: For the experiments described in this study, C57/BL10 wild-type mice were used and differences which were observed in both male and female mice were included in experiments. Animals were treated in respect to housing, nutrition and care according to the guidelines of Good laboratory Practice (GLP). All experimental protocols (Protocol N{degree sign} 7FF2C.4 -Authorization N{degree sign} 746/2016-PR) were approved and conformed to the regulatory standards. All animals were kept in a temperature of 22{degree sign}C {plus minus} 3{degree sign}C with a humidity between 50% and 60%, in animal cages with at least 5 animals.
Copyright
© 2021, Cipriano et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epigenetic regulation of Wnt7b expression by the cis-acting long noncoding RNA Lnc-Rewind in muscle stem cells
eLife 10:e54782.
https://doi.org/10.7554/eLife.54782
Further reading
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- Cancer Biology
- Cell Biology
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
