Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α

Gupta, Rana K.; Gao, Nan; Gorski, Regina; White, Peter; Hardy, Olga T.; Rafiq, Kiran; Brestelli, John; Chen, Guang; Stoeckert, Christian J.; Kaestner, Klaus H.

doi:10.1101/gad.1535507

Cited by 151 publications

(128 citation statements)

References 67 publications

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“…Isl-1 Chromatin Immunoprecipitation Assays-Approximately 800 to 1000 islets were isolated from five 8-week-old CD1 male mice using the standard collagenase procedure as described previously (25). The islets were washed in PBS, crosslinked in 1.1% formaldehyde, and sonicated in buffer containing 50 mM Tris-HCl (pH8.1), 10 mM EDTA, 0.05% SDS, and complete protease inhibitor mixture (Roche).…”

Section: Methodsmentioning

confidence: 99%

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

Liu

Hunter

et al. 2011

Journal of Biological Chemistry

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Aristaless related homeodomain protein (Arx) specifies the formation of the pancreatic islet ␣-cell during development. This cell type produces glucagon, a major counteracting hormone to insulin in regulating glucose homeostasis in adults. However, little is known about the factors that regulate Arx transcription in the pancreas. In this study, we showed that the number of Arx ؉ cells was significantly reduced in the pancreata of embryos deficient for the Islet-1 (Isl-1) transcription factor, which was also supported by the reduction in Arx mRNA levels. Chromatin immunoprecipitation analysis localized Isl-1 activator binding sites within two highly conserved noncoding regulatory regions (Re) in the Arx locus, termed Re1 (؉5.6 to ؉6.1 kb) and Re2 (؉23.6 to ؉24 kb). Using cell line-based transfection assays, we demonstrated that a Re1-and Re2-driven reporter was selectively activated in islet ␣-cells, a process mediated by Isl-1 in overexpression, knockdown, and site-directed mutation experiments. Moreover, Arx mRNA levels were upregulated in islet ␣-cells upon Isl-1 overexpression in vivo. Isl-1 represents the first known activator of Arx transcription in ␣-cells, here established to be acting through the conserved Re1 and Re2 control domains.Pancreatic islets play an important role in regulating carbohydrate metabolism through the production and secretion of hormones. The five cell types found in the islet are ␣-, ␤-, ␦-, ⑀-, and pancreatic polypeptide cells that, respectively, produce the hormones glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide (1). The hormonal products of the predominant ␣-and ␤-cells act in peripheral tissues in a counter-regulatory manner to control blood glucose homeostasis, with insulin promoting cellular glucose uptake and storage and glucagon promoting its release. Notably, although insulin resistance and ␤-cell dysfunction are the major causes of diabetes, the sustained, unregulated secretion of glucagon from ␣-cells also contributes to hyperglycemia and the associated complications (2-6). In fact, suppression of glucagon activity or levels has been shown to be a promising treatment for diabetics (3, 6 -9). Unfortunately, and in contrast to islet ␤-cells, our understanding of the factors involved in controlling ␣-cell differentiation and function is quite limited (1, 10).Glucagon ϩ cells first appear at embryonic day (E) 9.5 3 in mice, followed by insulin ϩ cells a day later (1). At around E13.5, a major expansion of a distinct population of hormone-producing cells begins to occur, with only these cells becoming mature islet ␣-and ␤-cells (11). A variety of distinct transcription factors are required during development for their production (1), including those that are necessary early in specifying the ␣-(e.g. Arx) and ␤-(e.g. Pax4 and Nkx6.1) lineages and others acting later in cell maintenance and maturation (e.g. MafB, Foxa2, Isl-1, and Pdx1) (12)(13)(14)(15)(16)(17)(18)(19)(20).Arx plays an essential role in islet ␣-cell formation. Expression of this transcrip...

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Section: Methodsmentioning

confidence: 99%

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

Liu

Hunter

et al. 2011

Journal of Biological Chemistry

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“…Gli2* lacks the 328 N-terminal amino acids of Gli2 and has been shown to be a 30 times more potent transactivator in co-transfection assays than Gli2 (18). Luciferase assays were performed as described previously (17).…”

Section: Methodsmentioning

confidence: 99%

FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine

Madison

McKenna

Dolson

et al. 2009

Journal of Biological Chemistry

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125

108

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The hedgehog (Hh) signaling pathway is a key component of cross-talk during vertebrate gut development, involving endodermally secreted Sonic (Shh) and Indian hedgehog (Ihh) proteins that directly signal to adjacent mesoderm. Here we show that the closely linked mesenchymal forkhead transcription factors Foxf1 and Foxl1 are part of this signaling cascade. Analysis of conserved non-coding sequences surrounding Foxf1 and Foxl1 identified seven Gli binding sites, with two sites near Foxl1 being identical among mammalian, bird, fish, and amphibian species. In vitro experiments indicate that Gli2 binds to these Gli sites, several of which are critical for Gli2-mediated activation of a luciferase reporter in 293 cells. In addition, we demonstrate occupancy of one of these elements by Gli proteins in the intestine in vivo using chromatin immunoprecipitation. Furthermore, expression of both Foxf1 and Foxl1 is reduced in the Gli2/Gli3 mutant gut. These results provide compelling evidence that Foxf1 and Foxl1 are mediators of the Hh (endoderm) to mesoderm signaling pathway.

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“…We have focused on hepatocyte nuclear factor 4-α (HNF-4α), a transcription factor from the nuclear hormone receptor superfamily, which is required for pancreatic β-cell differentiation and glucose homeostasis (12). HNF-4α has been linked to the development of a number of forms of T2D (13)(14)(15)(16)(17). Several HNF-4α protein variants arise from mRNAs transcribed from two promoters, proximal P1 and distal P2 (18) (Fig.…”

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.

303

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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Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α

Cited by 151 publications

References 67 publications

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine

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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