title: Role of Hepatic-Specific Transcription Factors and Polycomb Repressive Complex 2 during Induction of Fibroblasts to Hepatic Fate.
abstract: Direct reprogramming using defined sets of transcription factors (TFs) is a recent strategy for generating induced hepatocytes (iHeps) from fibroblasts for use in regenerative medicine and drug development. Comprehensive studies detailing the regulatory role of TFs during this reprogramming process could help increase its efficiency. This study aimed to find the TFs with the greatest influences on the generation of iHeps from fibroblasts, and to further understand their roles in the regulation of the gene expression program. Here, we used systems biology approaches to analyze high quality expression data sets in combination with TF-binding sites data and protein-protein interactions data during the direct reprogramming of fibroblasts to iHeps. Our results revealed two main patterns for differentially expressed genes (DEGs): up-regulated genes were categorized as hepatic-specific pattern, and down-regulated genes were categorized as mesoderm- and fibroblast-specific pattern. Interestingly, hepatic-specific genes co-expressed and were regulated by hepatic-specific TFs, specifically Hnf4a and Foxa2. Conversely, the mesoderm- and fibroblast-specific pattern was mainly silenced by polycomb repressive complex 2 (PRC2) members, including Suz12, Mtf2, Ezh2, and Jarid2. Independent analysis of both the gene and core regulatory network of DE-TFs showed significant roles for Hnf4a, Foxa2, and PRC2 members in the regulation of the gene expression program and in biological processes during the direct conversion process. Altogether, using systems biology approaches, we clarified the role of Hnf4a and Foxa2 as hepatic-specific TFs, and for the first time, introduced the PRC2 complex as the main regulator that favors the direct reprogramming process in cooperation with hepatic-specific factors.
authors.affiliation: Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
authors.forename: Shima
authors.initials: S
authors.lastname: Rastegar-Pouyani
authors.affiliation: Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
authors.forename: Niusha
authors.initials: N
authors.lastname: Khazaei
authors.affiliation: Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Wee
authors.affiliation: Department of Human Genetics, Division of Hematology and Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Abdulshakour
authors.identifier: http://orcid.org/0000-0003-1982-3958
authors.initials: A
authors.lastname: Mohammadnia
authors.affiliation: Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montreal, Quebec, Canada.|Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Moein
authors.initials: M
authors.lastname: Yaqubi
mesh_terms: D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology*; D053263:Gene Regulatory Networks; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D009928:Organ Specificity; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D060066:Protein Interaction Maps; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2