Suzuki Takahiro, Furuhata Erina, Maeda Shiori, Kishima Mami, Miyajima Yurina, Tanaka Yuki, Lim Joanne, Nishimura Hajime, Nakanishi Yuri, Shojima Aiko, Suzuki Harukazu
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrated Medical Science (IMS), RIKEN Yokohama Campus, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
Commun Biol. 2022 May 4;5(1):414. doi: 10.1038/s42003-022-03365-1.
Hepatocytes are the dominant cell type in the human liver, with functions in metabolism, detoxification, and producing secreted proteins. Although gene regulation and master transcription factors involved in the hepatocyte differentiation have been extensively investigated, little is known about how the epigenome is regulated, particularly the dynamics of DNA methylation and the critical upstream factors. Here, by examining changes in the transcriptome and the methylome using an in vitro hepatocyte differentiation model, we show putative DNA methylation-regulating transcription factors, which are likely involved in DNA demethylation and maintenance of hypo-methylation in a differentiation stage-specific manner. Of these factors, we further reveal that GATA6 induces DNA demethylation together with chromatin activation in a binding-site-specific manner during endoderm differentiation. These results provide an insight into the spatiotemporal regulatory mechanisms exerted on the DNA methylation landscape by transcription factors and uncover an epigenetic role for transcription factors in early liver development.
肝细胞是人类肝脏中的主要细胞类型，具有代谢、解毒和分泌蛋白质的功能。尽管已经对参与肝细胞分化的基因调控和主要转录因子进行了广泛研究，但对于表观基因组如何被调控，特别是DNA甲基化的动态变化以及关键的上游因子，我们知之甚少。在这里，通过使用体外肝细胞分化模型检测转录组和甲基化组的变化，我们发现了可能参与DNA去甲基化以及在分化阶段特异性维持低甲基化状态的DNA甲基化调控转录因子。在这些因子中，我们进一步揭示，在内胚层分化过程中，GATA6以结合位点特异性的方式诱导DNA去甲基化并伴随染色质激活。这些结果为转录因子对DNA甲基化格局施加的时空调控机制提供了见解，并揭示了转录因子在早期肝脏发育中的表观遗传作用。
