在人肝星状细胞中表达的长链非编码RNA与细胞外基质蛋白形成网络。
Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins.
作者信息
Zhou Chan, York Samuel R, Chen Jennifer Y, Pondick Joshua V, Motola Daniel L, Chung Raymond T, Mullen Alan C
机构信息
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
出版信息
Genome Med. 2016 Mar 23;8(1):31. doi: 10.1186/s13073-016-0285-0.
BACKGROUND
Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis.
METHODS
We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types.
RESULTS
We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease.
CONCLUSIONS
lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease.
背景
肝纤维化是几乎所有形式的慢性肝病发展为肝硬化和肝衰竭的根本原因，肝星状细胞（HSCs）是导致纤维化的主要细胞类型。长链非编码RNA（lncRNAs）越来越被认为是发育和疾病的调节因子；然而，关于它们在人HSCs中的表达及其在肝纤维化中的作用知之甚少。
方法
我们对RNA转录本进行了RNA测序和从头组装，以确定在人HSC肌成纤维细胞中表达的lncRNAs。我们分析了染色质免疫沉淀数据和表达数据，以鉴定受转化生长因子β（TGF-β）信号调节、与超级增强子相关且与43种人类组织和细胞类型相比在HSCs中表达受限的lncRNAs。进行共表达网络分析以发现lncRNAs的功能模块，并使用主成分分析和K均值聚类来比较HSCs与其他肌成纤维细胞类型中lncRNA的表达。
结果
我们鉴定出超过3600种在人HSC肌成纤维细胞中表达的lncRNAs。许多lncRNAs受主要纤维化信号TGF-β调节，并与编码细胞外基质（ECM）关键成分的基因形成网络，而ECM是纤维化瘢痕的底物。受TGF-β信号直接调节的lncRNAs在超级增强子处也富集。与43种其他人类组织和细胞类型相比，在HSCs中鉴定出的400多种lncRNAs在HSCs中独特表达，并且HSC肌成纤维细胞与源自其他组织的肌成纤维细胞相比表现出不同的lncRNA表达模式。共表达分析确定了一组与胶原基因紧密相连的lncRNAs以及在纤维化瘢痕形成过程中调节ECM的众多蛋白质。最后，我们鉴定出在人类肝病进展过程中诱导产生的lncRNAs。
结论
lncRNAs可能是人类肝病纤维化形成和进展的关键因素。
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