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Sci Rep. 2019 Mar 5;9(1):3562. doi: 10.1038/s41598-019-39215-0.

Extensive reprogramming of the nascent transcriptome during iPSC to hepatocyte differentiation.

Author information

1
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland. leena.viiri@staff.uta.fi.
2
Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
3
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
4
Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
5
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70211, Finland.
6
Heart Center, Tampere University Hospital, Tampere, 33520, Finland.

Abstract

Hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells (iPSCs) provide a renewable source of cells for drug discovery, disease modelling and cell-based therapies. Here, by using GRO-Seq we provide the first genome-wide analysis of the nascent RNAs in iPSCs, HLCs and primary hepatocytes to extend our understanding of the transcriptional changes occurring during hepatic differentiation process. We demonstrate that a large fraction of hepatocyte-specific genes are regulated at transcriptional level and identify hundreds of differentially expressed non-coding RNAs (ncRNAs), including primary miRNAs (pri-miRNAs) and long non-coding RNAs (lncRNAs). Differentiation induced alternative transcription start site (TSS) usage between the cell types as evidenced for miR-221/222 and miR-3613/15a/16-1 clusters. We demonstrate that lncRNAs and coding genes are tightly co-expressed and could thus be co-regulated. Finally, we identified sets of transcriptional regulators that might drive transcriptional changes during hepatocyte differentiation. These included RARG, E2F1, SP1 and FOXH1, which were associated with the down-regulated transcripts, and hepatocyte-specific TFs such as FOXA1, FOXA2, HNF1B, HNF4A and CEBPA, as well as RXR, PPAR, AP-1, JUNB, JUND and BATF, which were associated with up-regulated transcripts. In summary, this study clarifies the role of regulatory ncRNAs and TFs in differentiation of HLCs from iPSCs.

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