The long noncoding RNA Wisper controls cardiac fibrosis and remodeling.
The long noncoding RNA Wisper controls cardiac fibrosis and remodeling.
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DOI：
10.1126/scitranslmed.aai9118
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发表时间：
2017-06-21
影响因子：
17.1
通讯作者：
Pedrazzini T
中科院分区：
文献类型：
--
作者：
Micheletti R;Plaisance I;Abraham BJ;Sarre A;Ting CC;Alexanian M;Maric D;Maison D;Nemir M;Young RA;Schroen B;González A;Ounzain S;Pedrazzini T
长链非编码RNA（lncRNA）是心脏发育和疾病的重要调控因子。然而，我们对这些分子在心脏纤维化中的重要性的理解是有限的。使用整合的基因组筛选，我们鉴定了Wisper（Wisp2超级增强子相关RNA）作为心脏成纤维细胞富集的lncRNA，其调节损伤后的心脏纤维化。Wisper表达与心肌梗死（MI）小鼠模型和患有主动脉瓣狭窄的人类患者的心脏组织中的心脏纤维化相关。使用修饰的反义寡核苷酸（ASO）的体外功能丧失方法表明，Wisper是心脏成纤维细胞增殖、迁移和存活的特异性调节剂。因此，ASO介导的Wisper在体内的沉默减弱了MI诱导的纤维化和心功能障碍。在功能上，Wisper调节心脏成纤维细胞基因表达程序，这些程序对细胞特性、细胞外基质沉积、增殖和存活至关重要。此外，其与TIA1相关蛋白的结合使其能够控制赖氨酰羟化酶2的促纤维化形式的表达，这与胶原交联和基质稳定有关。总之，我们的研究结果将Wisper鉴定为心脏成纤维细胞富集的超级增强子相关lncRNA，其代表了一种有吸引力的治疗靶点，以减少心肌梗死后心脏纤维化的病理发展，并预防受损心脏的不良重塑。
Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer–associated RNA) as a cardiac fibroblast–enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO-mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix. Together, our findings identify Wisper as a cardiac fibroblast–enriched super-enhancer–associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart.
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影响因子：
5
作者：
Lighthouse JK;Small EM
通讯作者：
Small EM
影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
8.3
作者：
Lopez, Begona;Querejeta, Ramon;Diez, Javier
通讯作者：
Diez, Javier