Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development

Li, Tingting; Huang, Jian; Jiang, Ying; Zeng, Yan; He, Fuchu; Zhang, Michael Q.; Han, Ze‐Guang; Zhang, Xuegong

doi:10.1016/j.ygeno.2008.10.006

Cited by 65 publications

(98 citation statements)

References 12 publications

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“…This is in agreement with studies of in vivo liver tissues (6,24,28,29). Furthermore, similar results of clusters of genes that are either not expressed or low in hPSC-HEP compared with primary hepa- tocytes are shown in (14), indicating remaining immature features of hPSC-HEP.…”

Section: Discussionsupporting

confidence: 91%

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

Ghosheh

Küppers-Munther

Asplund

et al. 2017

Physiological Genomics

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Section: Discussionsupporting

confidence: 91%

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

Ghosheh

Küppers-Munther

Asplund

et al. 2017

Physiological Genomics

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“…However, not all the induction experiments succeed, and the intrinsic explanation is not fully clarified (19,20). On the basis of their characteristics, we presumed that developmental stage-specific hepatocytes, in theory, should have the ability to direct and induce maturation of tumor cells (21). The question of whether developmental stage-specific hepatocytes could induce the maturation of HepG2 cells has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit. is believed to be a controller and marker of mature hepatocytes (27,28). As a downstream target of HNF-4α, HNF-1α is also essential for hepatocyte maturation (29,30). USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate 33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A). Because the transcription factor binding sites are generally believed to scatter within 10 kb upstream of the transcriptional start site (34), the 10-kb gene promoters were all analyzed. On the basis of previous reports (25), the predicted binding sites of HNF-4α HNF-1α, HNF-6 and USF-1 were identified, respectively ( Figure 1B). It remains unknown whether developmental stage-specific hepatocytes rebuild the regulatory circuit to induce the maturation of HepG2 cells.In this study, HepG2 cells were cocultured with mouse embryonic hepatocytes at gestation of 12.5-15.5 d, because the mouse hepatocytes differentiated at 12.5 d, and the liver structure became firmly established between 12 and 15 d of gestation (35)(36)(37). The induced maturation of HepG2 cel...

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“…Advantages of these models include rapid growth, easy maintenance, and the development of genetic manipulation techniques for mechanistic studies with gain-of-function and loss-of-function strategies. Several researchers have examined the ontogenic gene expression profiles of a few P450s in mouse or rat liver (Choudhary et al, 2004;Alcorn et al, 2007;Cherala et al, 2007;Hart et al, 2009;Li et al, 2009a). Developmental expression patterns of some P450s in mice and rats are similar to those in humans.…”

Section: Introductionmentioning

confidence: 99%

RNA Sequencing Reveals Dynamic Changes of mRNA Abundance of Cytochromes P450 and Their Alternative Transcripts during Mouse Liver Development

Peng¹,

Yoo²,

Gunewardena³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Cytochromes P450 (P450s) are a superfamily of enzymes that have critical functions in liver to catalyze the biotransformation of numerous drugs. However, the functions of most P450s are not mature at birth, which can markedly affect the metabolism of drugs in newborns. Therefore, characterization of the developmental profiles and regulatory mechanisms of P450 expression is needed for more rational drug therapy of pediatric patients. An animal model is indispensable for studying the mechanisms of postnatal development of the P450s. Hence we used RNA sequencing (RNA-Seq) to provide a "true quantification" of mRNA expression of all P450s in mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used. Total mRNAs of the 103 mouse P450s displayed two rapid increasing stages after birth, reflecting critical functional transition of liver during development. Four ontogenic expression patterns were identified among the 71 significantly expressed P450s, which categorized genes into neonatal-, adolescent-, adolescent/adult-, and adult-enriched groups. The 10 most highly expressed subfamilies of mouse P450s in livers of adult mice were CYP2E, -2C, -2D, -3A, -4A, -2F, -2A, -1A, -4F, and -2B, which showed diverse expression profiles during development. The expression patterns of multiple members within a P450 subfamily were often classified to different groups. RNA-Seq also enabled the quantification of known transcript variants of CYP2C44, CYP2C50, CYP2D22, CYP3A25, and CYP26B1 and identification of novel transcripts for CYP2B10, CYP2D26, and CYP3A13. In conclusion, this study reveals the mRNA abundance of all the P450s in mouse liver during development and provides a foundation for mechanistic studies in the future.

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Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development

Cited by 65 publications

References 12 publications

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

RNA Sequencing Reveals Dynamic Changes of mRNA Abundance of Cytochromes P450 and Their Alternative Transcripts during Mouse Liver Development

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