(2020/10/28)

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Mysteries hidden in hepatic reprogramming
Researchers get clearer picture of how just two proteins can make fibroblasts convert intoliver-like cells
Researchers in Japan have elucidated the molecular mechanisms of a process to turn cells
called fibroblasts into those displaying functions similar to liver cells in mice, providing new
insights for using such cells in medicine and for understanding liver diseases related to thedisruption of cell formation.
Scientists have been exploring ways to generate various types of cells in the body for medical
purposes, and one common approach is to induce cells to switch to an intermediate phase fromwhich they can be programmed into any cell type.
However, Atsushi Suzuki, professor of Kyushu University’s Medical Institute of Bioregulation,
previously succeeded in directly reprogramming mouse fibroblasts, a type of cells that form thestructural network in tissues, into cells exhibiting properties of liver cells by introducing theright set of two transcription factors—proteins that play a key role in determining which genes
of DNA are turned on and off.
Referred to as induced hepatocyte-like cells or iHep cells, the reprogrammed cells are promisingfor use in treating liver diseases and as a tool for understanding how liver cells form, but thedetailed mechanisms for this conversion have remained a mystery.
“That just two transcription factors can make such sudden and drastic changes to a cell’sfunction is astounding,” says Suzuki. “After nine years of researching this mysterious
phenomenon, we are finally getting a clearer picture of how this happens.”
Following an integrative analysis, Suzuki’s research team in collaboration with researchers atKyoto University and the National Center for Global Health and Medicine have now unraveled
the series of dynamic cellular state changes leading to this reprogramming.
Investigating three sets of two transcription factors—Hnf4α and one of Foxa1, Foxa2, orFoxa3—capable of triggering the conversion, the researchers found that all three Foxa proteinsact as “pioneer factors” that open a specific region of DNA in tightly packed structures called
chromatin and then recruit Hnf4α to further open the regions.
However, while Foxa1 and Foxa2 appear to stay in the same location, Foxa3 then immediately
moves to the vicinity of transcription start sites—the beginning of DNA portions encoding
target genes—with Hnf4α. There, Foxa3 binds to a group of molecules that reads the DNA tocreate RNA based on the DNA template and moves with this molecular machinery, known as
RNA polymerase II, and Hnf4α along the DNA to efficiently induce transcriptional activation oftarget genes.
This unique feature of Foxa3 is indispensable for inducing conversion of fibroblasts to iHep cells
using Hnf4α and Foxa3, and this knowledge could help to decipher the various roles of the Foxa
proteins at different stages of development.
Understanding of the molecular mechanisms for iHep cell induction may provide insights into
the medical applications of iHep cells and lead to elucidation of the molecular basis forregulating hepatocyte differentiation during liver development and regeneration andpathogenesis of liver diseases caused by disruption of hepatocyte differentiation.
###For more information about this research, see “The dynamics of transcriptional activation by
hepatic reprogramming factors,” Kenichi Horisawa, Miyako Udono, Kazuko Ueno, Yasuyuki
Ohkawa, Masao Nagasaki, Sayaka Sekiya, and Atsushi Suzuki, Molecular Cell (2020).
https://doi.org/10.1016/j.molcel.2020.07.012

Foxa3 induces the expression of its target genes in a manner different from those of other family members,
Foxa1 and Foxa2. iHep cells induced from fibroblasts using Hnf4α and Foxa1, Hnf4α and Foxa2, and Hnf4α andFoxa3 are designated iHep-4α1, iHep-4α2, and iHep-4α3, respectively. TSS: transcription start site, Pol2: RNApolymerase II.
[Contact]<For Research Contents>

Atsushi Suzuki, Ph.D., Professor
Division of Organogenesis and Regeneration
Medical Institute of Bioregulation, Kyushu University
3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, JAPANTEL: +81-92-642-6449
FAX: +81-92-642-6444
E-mail: suzukicks@bioreg.kyushu-u.ac.jp<For Press>
Public Relations Office, Kyushu University
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