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FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

ABSTRACT: Pancreatic endocrine cell development into differentiated α- and β-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of α- and β-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate that Fcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by β-cell-specific FCoR overexpression (FcorKO-βFcor), and exhibit β-to-α-cell conversion. Compared with FcorKO, β-cell-specific Foxo1 knockout in the FcorKO (DKO) led to decreased Arx expression and α-cell mass. Foxo1 binding to Arx promoter led to DNA methyltransferase 3a (Dnmt3a) dissociation, Arx promoter hypomethylation, and increased Arx expression. In contrast, FCoR suppressed Arx through Foxo1 inhibition and Dnmt3a recruitment to Arx promoter and increased Arx promoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic α-cell mass by suppressing Arx expression.

SUBMITTER: Kodani N

PROVIDER: S-EPMC6951314 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

Kodani Noriko N Nakae Jun J Kobayashi Masaki M Kikuchi Osamu O Kitamura Tadahiro T Itoh Hiroshi H

iScience 20191223 1

Pancreatic endocrine cell development into differentiated α- and β-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of α- and β-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate that Fcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factor Aristaless-related hom ...[more]

PMID: 31923647

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Project description:ObjectiveCD36 is a scavenger and antiangiogenic receptor that is important in atherothrombotic diseases, diabetes mellitus, cancer, and obesity. Lysophosphatidic acid, a phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by downregulating endothelial CD36 transcription via protein kinase D1 (PKD-1) signaling. We aimed to understand mechanisms by which lysophosphatidic acid-mediated angiogenic signaling is integrated to regulate CD36 transcription and endothelial cell function via a nuclear transcriptional complex.Approach and resultsMicrovascular endothelial cells expressing CD36 were used for studying angiogenic signaling and CD36 transcription. Gene transfection and transduction, RT-qPCR, avidin-biotin-conjugated DNA-binding assay, chromatin immunoprecipitation assay, co-immunoprecipitation, proximal ligation assay, and immunofluorescence microscopy showed that lysophosphatidic acid-mediated CD36 transcriptional repression involved PKD-1 signaling mediated formation of forkhead box protein O1-histone deacetylase 7 complex in the nucleus. Unexpectedly, turning off CD36 transcription initiated reprogramming microvascular endothelial cells to express ephrin B2, a critical molecular signature involved in angiogenesis and arteriogenesis. Spheroid-based angiogenesis and in vivo Matrigel angiogenesis assays indicated that angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. A mouse tumor angiogenesis model revealed enhanced PKD-1 signaling and expression of ephrin B2 and smooth muscle actin in neovessels of Lewis Lung Carcinomas, along with low-CD36 expression or CD36 deficiency.ConclusionsLysophosphatidic acid/PKD-1 signaling leads to nuclear accumulation of histone deacetylase 7, where it interacts with forkhead box protein O1 to suppress endothelial CD36 transcription and mediates silencing of antiangiogenic switch, resulting in proangiogenic and proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for ischemic cardiovascular disease and cancer.

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FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

Publications

FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

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