HNF4A Regulates the Formation of Hepatic Progenitor Cells from Human iPSC-Derived Endoderm by Facilitating Efficient Recruitment of RNA Pol II

Genes (Basel). 2018 Dec 28;10(1):21. doi: 10.3390/genes10010021.

Ann DeLaForest ¹, Francesca Di Furio ², Ran Jing ³ ⁴, Amy Ludwig-Kubinski ⁵, Kirk Twaroski ⁶, Amanda Urick ⁷ ⁸, Kirthi Pulakanti ⁹, Sridhar Rao ¹⁰, Stephen A Duncan ¹¹ ¹²

Affiliations

1 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
2 Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Basic Science Building BS657A, 173 Ashley Ave, MSC 508, Charleston, SC 29425, USA. [email protected].
3 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
4 Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Basic Science Building BS657A, 173 Ashley Ave, MSC 508, Charleston, SC 29425, USA. [email protected].
5 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
6 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
7 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
8 Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Basic Science Building BS657A, 173 Ashley Ave, MSC 508, Charleston, SC 29425, USA. [email protected].
9 Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, 8733 Watertown Plank Road, WI 53226, USA. [email protected].
10 Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, 8733 Watertown Plank Road, WI 53226, USA. [email protected].
11 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. [email protected].
12 Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Basic Science Building BS657A, 173 Ashley Ave, MSC 508, Charleston, SC 29425, USA. [email protected].

PMID: 30597922 DOI: 10.3390/genes10010021

Abstract

Elucidating the molecular basis of cell differentiation will advance our understanding of organ development and disease. We have previously established a protocol that efficiently produces cells with hepatocyte characteristics from human induced pluripotent stem cells. We previously used this cell differentiation model to identify the transcription factor hepatocyte nuclear factor 4 α (HNF4A) as being essential during the transition of the endoderm to a hepatic fate. Here, we sought to define the molecular mechanisms through which HNF4A controls this process. By combining HNF4A chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) analyses at the onset of hepatic progenitor cell formation with transcriptome data collected during early stages of differentiation, we identified genes whose expression is directly dependent upon HNF4A. By examining the dynamic changes that occur at the promoters of these HNF4A targets we reveal that HNF4A is essential for recruitment of RNA polymerase (RNA pol) II to genes that are characteristically expressed as the hepatic progenitors differentiate from the endoderm.

Keywords

hepatocyte differentiation; induced pluripotent stem cells; liver development; transcription.

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