Regulatory network changes between cell lines and their tissues of origin

BMC Genomics

Research Article

Abhijeet R. Sonawane¹  Dawn L. DeMeo²  Camila M. Lopes-Ramos³  Maud Fagny³  Cho-Yi Chen³  John Platig³  Joseph N. Paulson³  Marieke L. Kuijjer³  Kimberly Glass⁴  John Quackenbush⁵ 

[1] Channing Division of Network Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Channing Division of Network Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA;Channing Division of Network Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA;Channing Division of Network Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Department of Cancer Biology, Dana-Farber Cancer Institute, 02215, Boston, MA, USA;

关键词: Regulatory networks;    Transcriptome;    GTEx;    Lymphoblastoid cell lines;    Fibroblast cell lines;   

DOI  :  10.1186/s12864-017-4111-x

 received in 2017-04-05, accepted in 2017-09-01,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCell lines are an indispensable tool in biomedical research and often used as surrogates for tissues. Although there are recognized important cellular and transcriptomic differences between cell lines and tissues, a systematic overview of the differences between the regulatory processes of a cell line and those of its tissue of origin has not been conducted. The RNA-Seq data generated by the GTEx project is the first available data resource in which it is possible to perform a large-scale transcriptional and regulatory network analysis comparing cell lines with their tissues of origin.ResultsWe compared 127 paired Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs) and whole blood samples, and 244 paired primary fibroblast cell lines and skin samples. While gene expression analysis confirms that these cell lines carry the expression signatures of their primary tissues, albeit at reduced levels, network analysis indicates that expression changes are the cumulative result of many previously unreported alterations in transcription factor (TF) regulation. More specifically, cell cycle genes are over-expressed in cell lines compared to primary tissues, and this alteration in expression is a result of less repressive TF targeting. We confirmed these regulatory changes for four TFs, including SMAD5, using independent ChIP-seq data from ENCODE.ConclusionsOur results provide novel insights into the regulatory mechanisms controlling the expression differences between cell lines and tissues. The strong changes in TF regulation that we observe suggest that network changes, in addition to transcriptional levels, should be considered when using cell lines as models for tissues.

【 授权许可】

CC BY   
© The Author(s). 2017