Role of Hepatic-Specific Transcription Factors and Polycomb Repressive Complex 2 during Induction of Fibroblasts to Hepatic Fate
| Autor: | Abdulshakour Mohammadnia, Niusha Khazaei, Moein Yaqubi, Ping Wee, Shima Rastegar-Pouyani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteomics Gene regulatory network lcsh:Medicine Gene Expression Biochemistry Animal Cells SUZ12 Medicine and Health Sciences Gene Regulatory Networks Protein Interaction Maps lcsh:Science Connective Tissue Cells Regulation of gene expression Multidisciplinary Polycomb Repressive Complex 2 Cellular Reprogramming Cell biology medicine.anatomical_structure Liver Connective Tissue Organ Specificity Protein Interaction Networks Cellular Types Anatomy Reprogramming Network Analysis Research Article Mesoderm Computer and Information Sciences Systems biology Biology 03 medical and health sciences Gene Types medicine Genetics Humans Gene Regulation Protein Interactions Transcription factor lcsh:R Biology and Life Sciences Proteins Computational Biology Cell Biology Fibroblasts 030104 developmental biology Biological Tissue Protein-Protein Interactions Hepatocytes Regulator Genes lcsh:Q FOXA2 Transcription Factors |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 11, p e0167081 (2016) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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