@article{630e97de586c406bbd674aab2f7b4bd2,
title = "A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease",
abstract = "Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.",
keywords = "Gene network, Hepatology, Systems biology",
author = "Hong Yang and Muhammad Arif and Meng Yuan and Xiangyu Li and Koeun Shong and Hasan T{\"u}rkez and Jens Nielsen and Mathias Uhl{\'e}n and Jan Bor{\'e}n and Cheng Zhang and Adil Mardinoglu",
note = "Funding Information: A.M. and H.Y. acknowledge support from the PoLiMeR Innovative Training Network (Marie Sk?odowska-Curie Grant Agreement No. 812616) which has received funding from the European Union's Horizon 2020 research and innovation program. The authors would like to acknowledge financially support from ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (No. 72110). The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project sllstore2017024. We would like to thank Dr. Theo Portlock for the comments on the manuscript. Conceptualization, A.M. C.Z. and H.Y.; methodology, software, and formal analysis, H.Y. M.A. and M.Y.; investigation, H.Y. M.A. M.Y. and C.Z.; writing-original draft, H.Y.; writing - review & editing, H.Y. M.A. M.Y. X.L. K.S. H.T. J.N. M.U. J.B. C.Z. and A.M.; funding acquisition, A.M.; supervision, C.Z. and A.M. A.M. J.B. and M.U. are the founder and shareholders of ScandiBi3o Therapeutics and they filed a patent application on the use of CMA to treat NAFLD patients. The other authors declare no conflict of interest. Funding Information: A.M. and H.Y. acknowledge support from the PoLiMeR Innovative Training Network (Marie Sk{\l}odowska-Curie Grant Agreement No. 812616 ) which has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program. The authors would like to acknowledge financially support from ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation (No. 72110 ). The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project sllstore2017024. We would like to thank Dr. Theo Portlock for the comments on the manuscript. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "19",
doi = "10.1016/j.isci.2021.103222",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier publishing company",
number = "11",
}