Genome-Wide Mapping of Bivalent Histone Modifications in Hepatic Stem/Progenitor Cells. (1st April 2019)

• Record Type: Journal Article
• Authors: Kanayama, Kengo; Chiba, Tetsuhiro; Oshima, Motohiko; Kanzaki, Hiroaki; Koide, Shuhei; Saraya, Atsunori; Miyagi, Satoru; Mimura, Naoya; Kusakabe, Yuko; Saito, Tomoko; Ogasawara, Sadahisa; Suzuki, Eiichiro; Ooka, Yoshihiko; Maruyama, Hitoshi; Iwama, Atsushi; Kato, Naoya
• Other Names: Najimi Mustapha Academic Editor.
• Is Part Of: Stem cells international. Volume 2019(2019)
• Publication Date: 2019-04-01
• Subjects: Stem Cells -- Periodicals; Stem Cells -- Therapeutic use -- Periodicals; Stem Cells -- Transplantation -- Periodicals; 616.0277405
• DOI: 10.1155/2019/9789240
• Languages: English
• ISSNs: 1687-966X

Abstract

Abstract : The "bivalent domain, " a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk + ) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including Cdkn2a and Sox4, were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of Sox4 in Dlk + cells suppressed colony propagation and resulted in increased numbers of albumin + /cytokeratin 7 + progenitor cells in colonies. These findings implicate that derepression of Sox4 expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells.