Foxa1 and Foxa2 regulate bile duct development in mice

Li, Zhaoyu; White, Peter; Tuteja, Geetu; Rubins, Nir; Sackett, Sara Dutton; Kaestner, Klaus H.

doi:10.1172/jci38201

Cited by 124 publications

(129 citation statements)

References 56 publications

(100 reference statements)

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“…Although the origin of hamartomas as well as the mechanism of their development in the Fbxw7-deficient liver are currently unclear, transient activation of Notch proteins as a result of Fbxw7 loss may lead to a shift in cell differentiation from hepatocytes to cholangiocytes, and the generation of such abnormally differentiated cells might confer a predisposition to hamartoma development that is realized if the cells undergo an additional gene mutation. Mice lacking both Foxa1 and Foxa2 were recently shown to display a similar liver phenotype (hyperplasia of the biliary tree) (56). However, neither differentiation of hepatocytes nor Notch signaling were affected in Foxa1/2-deficient mice, whereas hyperactivation of Notch signaling seems to be attributable to the bile duct hamartoma in Fbxw7-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver

et al. 2011

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E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cul1), S-phase kinase-associated protein 1 (Skp1), and a member of the F-box family of proteins. The identity of the F-box protein determines the substrate specificity of the complex. The F-box family member F-box-and WD repeat domain-containing 7 (Fbxw7; also known as Fbw7, SEL-10, hCdc4, and hAgo) targets for degradation proteins with wide-ranging functions, and uncovering its in vivo role has been difficult, because Fbxw7 -/-embryos die in utero. Using two different Cre-loxP systems (Mx1-Cre and Alb-Cre), we generated mice with liver-specific null mutations of Fbxw7. Hepatic ablation of Fbxw7 resulted in hepatomegaly and steatohepatitis, with massive deposition of triglyceride, a phenotype similar to that observed in humans with nonalcoholic steatohepatitis. Both cell proliferation and the abundance of Fbxw7 substrates were increased in the Fbxw7-deficient liver. Long-term Fbxw7 deficiency resulted in marked proliferation of the biliary system and the development of hamartomas. Fbxw7 deficiency also skewed the differentiation of liver stem cells toward the cholangiocyte lineage rather than the hepatocyte lineage in vitro. This bias was corrected by additional loss of the Notch cofactor RBP-J, suggesting that Notch accumulation triggered the abnormal proliferation of the biliary system. Together, our results suggest that Fbxw7 plays key roles, regulating lipogenesis and cell proliferation and differentiation in the liver.

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Section: Discussionmentioning

confidence: 99%

Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver

et al. 2011

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“…Post-developmentally, there are many examples of where prior binding by FoxA factors enables the subsequent binding by hormone receptors and other DNA-binding proteins (Gao et al 2003;Carroll et al 2005;Zhang et al 2005;Li et al 2009Li et al , 2012bPihlajamaa et al 2014), as previously covered in greater detail (Zaret and Carroll 2011). The mammalian circadian clock is driven by the CLOCK and BMAL1 transcription factors that rhythmically bind to nucleosomal target sites, promote incorporation of the histone variant H2A.Z, and enable the subsequent binding of other transcription factors (Menet et al 2014).…”

Section: Pioneer Factors In Cell Programming During Developmentmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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“…Il6 mRNA, a cytokine regulating Th1, Th2, and Th17 cell differentiation (51,52), was increased 4.6-fold in Foxa2 Δ/Δ mice. Recent studies demonstrated that Foxa2 bound to the Il6 promoter and suppressed Il6 expression in liver (53). Because multiple Th1-associated genes are altered in the Foxa2 Δ/Δ mice, it is presently unclear which play the dominant roles in the observed phenotype.…”

Section: Th2 Cytokine-dominated Inflammation Postdeletion Of Foxa2 Inmentioning

confidence: 99%