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Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins

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 developm...

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Autores principales: Zhou, Chan, York, Samuel R., Chen, Jennifer Y., Pondick, Joshua V., Motola, Daniel L., Chung, Raymond T., Mullen, Alan C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804564/
https://www.ncbi.nlm.nih.gov/pubmed/27007663
http://dx.doi.org/10.1186/s13073-016-0285-0
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author Zhou, Chan
York, Samuel R.
Chen, Jennifer Y.
Pondick, Joshua V.
Motola, Daniel L.
Chung, Raymond T.
Mullen, Alan C.
author_facet Zhou, Chan
York, Samuel R.
Chen, Jennifer Y.
Pondick, Joshua V.
Motola, Daniel L.
Chung, Raymond T.
Mullen, Alan C.
author_sort Zhou, Chan
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-016-0285-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-48045642016-03-24 Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins Zhou, Chan York, Samuel R. Chen, Jennifer Y. Pondick, Joshua V. Motola, Daniel L. Chung, Raymond T. Mullen, Alan C. Genome Med Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-016-0285-0) contains supplementary material, which is available to authorized users. BioMed Central 2016-03-23 /pmc/articles/PMC4804564/ /pubmed/27007663 http://dx.doi.org/10.1186/s13073-016-0285-0 Text en © Zhou et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhou, Chan
York, Samuel R.
Chen, Jennifer Y.
Pondick, Joshua V.
Motola, Daniel L.
Chung, Raymond T.
Mullen, Alan C.
Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title_full Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title_fullStr Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title_full_unstemmed Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title_short Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
title_sort long noncoding rnas expressed in human hepatic stellate cells form networks with extracellular matrix proteins
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804564/
https://www.ncbi.nlm.nih.gov/pubmed/27007663
http://dx.doi.org/10.1186/s13073-016-0285-0
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