Expression of HNF4α isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing

Torres-Padilla, Marı́a Elena; Fougère-Deschatrette, Catherine; Weiss, Mary C.

doi:10.1016/s0925-4773(01)00521-4

Cited by 92 publications

(121 citation statements)

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“…However, recent data suggest that these isoforms are expressed in a tissue-specific fashion, and that within a particular tissue the pattern of expression may depend on developmental stage. isoforms increase dramatically in late gestation and predominate in adult life [23]. In our experimental model, we found an increase in hepatic total Hnf4a mRNA following prenatal dexamethasone treatment.…”

Section: Discussionmentioning

confidence: 46%

“…Hnf4a potentially encodes at least nine distinct isoforms as a result of alternative promoter usage and differential splicing [22][23][24][25]. The developmental and physiological relevance of the various Hnf4a isoforms has not been fully explored, mainly because most previous studies relied on probes that failed to differentiate among the isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…Custom TaqMan Gene Expression Assay primers were used for Pck2 and Tcf1: Pck2, 5′-TGTCATCCGCAAGCTGAAGAA-3′ (forward), 5′-GCTTTCGATCCTGGCCACAT-3′ (reverse), and 5′-6-FAM-CCAGCCAACAGTTGTC-TAMRA-3′ (probe); Tcf1 5′-GAAGAGCGAGAGACCTTGGT-3′ (forward), 5′-GGTGACACCCCTCTCTGGAT-3′ (reverse), and 5′-6-FAM-CACTCCGCCCTATTGC-TAMRA-3′ (probe). Hnf4a potentially encodes nine distinct isoforms (Hnf4a1 to Hnf4a9) as a result of alternative promoter usage and differential splicing [22][23][24][25], and these isoforms are expressed in a tissue-specific manner. Embryonic/foetal liver predominantly expresses 'foetal' P2-promoter-initiated isoforms (Hnf4a7 and Hnf4a8), while Hnf4a1 and Hnf4a2 (driven by 'adult' P1 promoter) are first expressed later in gestation and predominate in the adult liver (Fig.…”

Section: Animalsmentioning

confidence: 99%

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Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

et al. 2006

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Aims/hypothesis: Prenatal glucocorticoid exposure causes lifelong hyperglycaemia in rat offspring, associated with permanently increased hepatic phosphoenolpyruvate carboxykinase 2 (PCK2), the rate-controlling enzyme of gluconeogenesis. To elucidate the mechanisms underlying the 'programming' of PCK2, this study examined the effect of prenatal dexamethasone treatment on expression of transcription factors that regulate Pck2. Materials and Methods: Real-time RT-PCR and in situ hybridisation were used to measure and localise hepatic mRNA transcribed from the genes for PCK2, hepatocyte nuclear factor 4, alpha (HNF4A), transcription factor 1 (TCF1), CCAAT/enhancer binding protein, alpha (CEBPA), CEBPB, the glucocorticoid receptor (NR3C1) and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A) in foetal and adult offspring of dams treated with dexamethasone or vehicle during the last week of gestation. Results: Prenatal dexamethasone exposure significantly elevated Hnf4a mRNA expression in foetal and adult liver. This resulted from increased expression of isoforms derived from the 'adult' (P1) Hnf4a promoter. In contrast, isoforms from the 'foetal' (P2) promoter were markedly suppressed by dexamethasone. Like Pck2, the increase in hepatic Hnf4a mRNA occurred exclusively in the periportal zone. Foetal Tcf1 expression was also increased by dexamethasone treatment, but this did not persist into adulthood. Prenatal dexamethasone did not affect the amounts of foetal and/or adult Cebpa, Cebpb, Nr3c1 or Ppargc1a mRNA. Conclusions/interpretation: Prenatal dexamethasone exposure caused a permanent increase in hepatic Hnf4a mRNA. This increase, which was associated with a premature switch from foetal to adult promoter predominance, was congruent with changes in Pck2 expression. These data suggest that HNF4A might mediate Pck2 overexpression and subsequent hyperglycaemia.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

et al. 2006

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“…The proximal P1 promoter drives the expression of the major isoforms in the adult hepatocyte, intestine and kidney (primarily HNF4α1 and HNF4α2); HNF4α2 differs from HNF4α1 by a 10 amino acid insertion in the C-terminal region (see Figure 1C). The distal P2 promoter drives the expression of isoforms present primarily in the embryonic liver and adult stomach and pancreas (primarily HNF4α7/8); HNF4α7/8 are 13 amino acids shorter than HNF4α1/2 due to a different N-terminus [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

Maeda

Hwang‐Verslues

Wei

et al. 2006

Biochemical Journal

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The liver is exposed to a wide variety of toxic agents, many of which damage DNA and result in increased levels of the tumour suppressor protein p53. We have previously shown that p53 inhibits the transactivation function of HNF (hepatocyte nuclear factor) 4α1, a nuclear receptor known to be critical for early development and liver differentiation. In the present study we demonstrate that p53 also down-regulates expression of the human HNF4α gene via the proximal P1 promoter. Overexpression of wild-type p53 down-regulated endogenous levels of both HNF4α protein and mRNA in Hep3B cells. This decrease was also observed when HepG2 cells were exposed to UV irradiation or doxorubicin, both of which increased endogenous p53 protein levels. Ectopically expressed p53, but not a mutant p53 defective in DNA binding (R249S), down-regulated HNF4α P1 promoter activity. Chromatin immunoprecipitation also showed that endogenous p53 bound the HNF4α P1 promoter in vivo after doxorubicin treatment. The mechanism by which p53 down-regulates the P1 promoter appears to be multifaceted. The down-regulation was partially recovered by inhibition of HDAC activity and appears to involve the positive regulator HNF6α. p53 bound HNF6α in vivo and in vitro and prevented HNF6α from binding DNA in vitro. p53 also repressed stimulation of the P1 promoter by HNF6α in vivo. However, since the R249S p53 mutant also bound HNF6α, binding HNF6α is apparently not sufficient for the repression. Implications of the p53-mediated repression of HNF4α expression in response to cellular stress are discussed.

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“…1A). The P2 promoter is important in early development and adult islets, whereas P1 is the main promoter in adult liver, kidney, and in- testine (19,20). Activation of the P1 promoter has been shown to involve a physical interaction with an upstream enhancer (21).…”

mentioning

confidence: 99%

Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets

Sandovici

Smith

Nitert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

302

219

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Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.maternal nutrition | developmental programming | DNA methylation | histone modifications | diet-gene interactions

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Expression of HNF4α isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing

Cited by 92 publications

References 45 publications

Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets

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