Cargando…

Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes

Human pluripotent stem cell-derived hepatocytes have the potential to provide in vitro model systems for drug discovery and hepatotoxicity testing. However, these cells are currently unsuitable for drug toxicity and efficacy testing because of their limited expression of genes encoding drug-metaboli...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Han-Jin, Choi, Young-Jun, Kim, Ji Woo, Chun, Hang-Suk, Im, Ilkyun, Yoon, Seokjoo, Han, Yong-Mahn, Song, Chang-Woo, Kim, Hyemin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503736/
https://www.ncbi.nlm.nih.gov/pubmed/26177506
http://dx.doi.org/10.1371/journal.pone.0132992
_version_ 1782381352174223360
author Park, Han-Jin
Choi, Young-Jun
Kim, Ji Woo
Chun, Hang-Suk
Im, Ilkyun
Yoon, Seokjoo
Han, Yong-Mahn
Song, Chang-Woo
Kim, Hyemin
author_facet Park, Han-Jin
Choi, Young-Jun
Kim, Ji Woo
Chun, Hang-Suk
Im, Ilkyun
Yoon, Seokjoo
Han, Yong-Mahn
Song, Chang-Woo
Kim, Hyemin
author_sort Park, Han-Jin
collection PubMed
description Human pluripotent stem cell-derived hepatocytes have the potential to provide in vitro model systems for drug discovery and hepatotoxicity testing. However, these cells are currently unsuitable for drug toxicity and efficacy testing because of their limited expression of genes encoding drug-metabolizing enzymes, especially cytochrome P450 (CYP) enzymes. Transcript levels of major CYP genes were much lower in human embryonic stem cell-derived hepatocytes (hESC-Hep) than in human primary hepatocytes (hPH). To verify the mechanism underlying this reduced expression of CYP genes, including CYP1A1, CYP1A2, CYP1B1, CYP2D6, and CYP2E1, we investigated their epigenetic regulation in terms of DNA methylation and histone modifications in hESC-Hep and hPH. CpG islands of CYP genes were hypermethylated in hESC-Hep, whereas they had an open chromatin structure, as represented by hypomethylation of CpG sites and permissive histone modifications, in hPH. Inhibition of DNA methyltransferases (DNMTs) during hepatic maturation induced demethylation of the CpG sites of CYP1A1 and CYP1A2, leading to the up-regulation of their transcription. Combinatorial inhibition of DNMTs and histone deacetylases (HDACs) increased the transcript levels of CYP1A1, CYP1A2, CYP1B1, and CYP2D6. Our findings suggest that limited expression of CYP genes in hESC-Hep is modulated by epigenetic regulatory factors such as DNMTs and HDACs.
format Online
Article
Text
id pubmed-4503736
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-45037362015-07-17 Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes Park, Han-Jin Choi, Young-Jun Kim, Ji Woo Chun, Hang-Suk Im, Ilkyun Yoon, Seokjoo Han, Yong-Mahn Song, Chang-Woo Kim, Hyemin PLoS One Research Article Human pluripotent stem cell-derived hepatocytes have the potential to provide in vitro model systems for drug discovery and hepatotoxicity testing. However, these cells are currently unsuitable for drug toxicity and efficacy testing because of their limited expression of genes encoding drug-metabolizing enzymes, especially cytochrome P450 (CYP) enzymes. Transcript levels of major CYP genes were much lower in human embryonic stem cell-derived hepatocytes (hESC-Hep) than in human primary hepatocytes (hPH). To verify the mechanism underlying this reduced expression of CYP genes, including CYP1A1, CYP1A2, CYP1B1, CYP2D6, and CYP2E1, we investigated their epigenetic regulation in terms of DNA methylation and histone modifications in hESC-Hep and hPH. CpG islands of CYP genes were hypermethylated in hESC-Hep, whereas they had an open chromatin structure, as represented by hypomethylation of CpG sites and permissive histone modifications, in hPH. Inhibition of DNA methyltransferases (DNMTs) during hepatic maturation induced demethylation of the CpG sites of CYP1A1 and CYP1A2, leading to the up-regulation of their transcription. Combinatorial inhibition of DNMTs and histone deacetylases (HDACs) increased the transcript levels of CYP1A1, CYP1A2, CYP1B1, and CYP2D6. Our findings suggest that limited expression of CYP genes in hESC-Hep is modulated by epigenetic regulatory factors such as DNMTs and HDACs. Public Library of Science 2015-07-15 /pmc/articles/PMC4503736/ /pubmed/26177506 http://dx.doi.org/10.1371/journal.pone.0132992 Text en © 2015 Park et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Park, Han-Jin
Choi, Young-Jun
Kim, Ji Woo
Chun, Hang-Suk
Im, Ilkyun
Yoon, Seokjoo
Han, Yong-Mahn
Song, Chang-Woo
Kim, Hyemin
Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title_full Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title_fullStr Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title_full_unstemmed Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title_short Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes
title_sort differences in the epigenetic regulation of cytochrome p450 genes between human embryonic stem cell-derived hepatocytes and primary hepatocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503736/
https://www.ncbi.nlm.nih.gov/pubmed/26177506
http://dx.doi.org/10.1371/journal.pone.0132992
work_keys_str_mv AT parkhanjin differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT choiyoungjun differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT kimjiwoo differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT chunhangsuk differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT imilkyun differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT yoonseokjoo differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT hanyongmahn differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT songchangwoo differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes
AT kimhyemin differencesintheepigeneticregulationofcytochromep450genesbetweenhumanembryonicstemcellderivedhepatocytesandprimaryhepatocytes