Targeting the nuclear long noncoding transcript LSP1P5 abrogates extracellular matrix deposition by trans-upregulating CEBPA in keloids
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - (2024) vom: 28. März |
Sprache: |
Englisch |
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Beteiligte Personen: |
Gu, Shuchen [VerfasserIn] |
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Links: |
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Themen: |
CEBPA |
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Anmerkungen: |
Date Revised 25.04.2024 published: Print-Electronic Citation Status Publisher |
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doi: |
10.1016/j.ymthe.2024.03.031 |
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funding: |
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PPN (Katalog-ID): |
NLM370433750 |
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520 | |a Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a CEBPA | |
650 | 4 | |a H3K27me3 | |
650 | 4 | |a LSP1P5 | |
650 | 4 | |a PRC2 | |
650 | 4 | |a RNA therapy | |
650 | 4 | |a chromosomal accessibility | |
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650 | 4 | |a skin fibrosis | |
700 | 1 | |a Huang, Xin |e verfasserin |4 aut | |
700 | 1 | |a Luo, Shenying |e verfasserin |4 aut | |
700 | 1 | |a Liu, Yunhan |e verfasserin |4 aut | |
700 | 1 | |a Khoong, Yimin |e verfasserin |4 aut | |
700 | 1 | |a Liang, Hsin |e verfasserin |4 aut | |
700 | 1 | |a Tu, Liying |e verfasserin |4 aut | |
700 | 1 | |a Xu, Ruoqing |e verfasserin |4 aut | |
700 | 1 | |a Yang, En |e verfasserin |4 aut | |
700 | 1 | |a Zhao, Yixuan |e verfasserin |4 aut | |
700 | 1 | |a Yao, Min |e verfasserin |4 aut | |
700 | 1 | |a Zan, Tao |e verfasserin |4 aut | |
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