scholarly journals Genetics of trans-regulatory variation in gene expression

2017 ◽  
Author(s):  
Frank W. Albert ◽  
Joshua S. Bloom ◽  
Jake Siegel ◽  
Laura Day ◽  
Leonid Kruglyak
Keyword(s):  
Gene Expression ◽  
Statistical Power ◽  
Target Genes ◽  
Transcriptome Profiling ◽  
Mrna Levels ◽  
Heritable Variation ◽  
Altered Expression ◽  
Regulatory Variation ◽  
Transcription Factor Genes ◽  
Transcriptome Variation

AbstractHeritable variation in gene expression provides a critical bridge between differences in genome sequence and the biology of many traits, including common human diseases. However, the sources of most regulatory genetic variation remain unknown. Here, we used transcriptome profiling in 1,012 yeast segregants to map the genetic basis of variation in gene expression with high statistical power. We identified expression quantitative trait loci (eQTL) that together account for over 70% of the total genetic contribution to variation in mRNA levels, allowing us to examine the sources of regulatory variation comprehensively. We found that variation in the expression of a typical gene has a complex genetic architecture involving multiple eQTL. We also detected hundreds of eQTL pairs with significant non-additive interactions in an unbiased genome-wide scan. Although most genes were influenced by a local eQTL located close to the gene, most expression variation arose from distant, trans-acting eQTL located far from their target genes. Nearly all distant eQTL clustered at 102 “hotspot” locations, some of which influenced the expression of thousands of genes. Hotspot regions were enriched for transcription factor genes and altered expression of their target genes though both direct and indirect mechanisms. Many local eQTL had no detectable effects on the expression of other genes in trans. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.

scholarly journals Genetics of trans-regulatory variation in gene expression

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Frank Wolfgang Albert ◽  
Joshua S Bloom ◽  
Jake Siegel ◽  
Laura Day ◽  
Leonid Kruglyak
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Genomic Variation ◽  
Mrna Levels ◽  
Heritable Variation ◽  
Expression Variation ◽  
Regulatory Variation ◽  
Transcription Factor Genes ◽  
Transcriptome Variation ◽  
In Trans

Heritable variation in gene expression forms a crucial bridge between genomic variation and the biology of many traits. However, most expression quantitative trait loci (eQTLs) remain unidentified. We mapped eQTLs by transcriptome sequencing in 1012 yeast segregants. The resulting eQTLs accounted for over 70% of the heritability of mRNA levels, allowing comprehensive dissection of regulatory variation. Most genes had multiple eQTLs. Most expression variation arose from trans-acting eQTLs distant from their target genes. Nearly all trans-eQTLs clustered at 102 hotspot locations, some of which influenced the expression of thousands of genes. Fine-mapped hotspot regions were enriched for transcription factor genes. While most genes had a local eQTL, most of these had no detectable effects on the expression of other genes in trans. Hundreds of non-additive genetic interactions accounted for small fractions of expression variation. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.

scholarly journals A CRISPR/Cas9 genome editing pipeline in the EndoC-βH1 cell line to study genes implicated in beta cell function

2019 ◽  
Vol 4 ◽  
pp. 150 ◽  
Author(s):  
Antje K. Grotz ◽  
Fernando Abaitua ◽  
Elena Navarro-Guerrero ◽  
Benoit Hastoy ◽  
Daniel Ebner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Beta Cell ◽  
Er Stress ◽  
Cell Line ◽  
Cell Lines ◽  
Target Genes ◽  
Gene Knockout ◽  
Mrna Levels ◽  
Beta Cell Line ◽  
Human Beta Cell

Type 2 diabetes (T2D) is a global pandemic with a strong genetic component, but most causal genes influencing the disease risk remain unknown. It is clear, however, that the pancreatic beta cell is central to T2D pathogenesis. In vitro gene-knockout (KO) models to study T2D risk genes have so far focused on rodent beta cells. However, there are important structural and functional differences between rodent and human beta cell lines. With that in mind, we have developed a robust pipeline to create a stable CRISPR/Cas9 KO in an authentic human beta cell line (EndoC-βH1). The KO pipeline consists of a dual lentiviral sgRNA strategy and we targeted three genes (INS, IDE, PAM) as a proof of concept. We achieved a significant reduction in mRNA levels and complete protein depletion of all target genes. Using this dual sgRNA strategy, up to 94 kb DNA were cut out of the target genes and the editing efficiency of each sgRNA exceeded >87.5%. Sequencing of off-targets showed no unspecific editing. Most importantly, the pipeline did not affect the glucose-responsive insulin secretion of the cells. Interestingly, comparison of KO cell lines for NEUROD1 and SLC30A8 with siRNA-mediated knockdown (KD) approaches demonstrate phenotypic differences. NEUROD1-KO cells were not viable and displayed elevated markers for ER stress and apoptosis. NEUROD1-KD, however, only had a modest elevation, by 34%, in the pro-apoptotic transcription factor CHOP and a gene expression profile indicative of chronic ER stress without evidence of elevated cell death. On the other hand, SLC30A8-KO cells demonstrated no reduction in KATP channel gene expression in contrast to siRNA silencing. Overall, this strategy to efficiently create stable KO in the human beta cell line EndoC-βH1 will allow for a better understanding of genes involved in beta cell dysfunction, their underlying functional mechanisms and T2D pathogenesis.

scholarly journals Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters

2019 ◽  
Author(s):  
Joanna Mitchelmore ◽  
Nastasiya Grinberg ◽  
Chris Wallace ◽  
Mikhail Spivakov
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Statistical Power ◽  
Target Genes ◽  
Allelic Variation ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Distal Enhancer ◽  
Association Testing ◽  
Gene Regulatory

AbstractIdentifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritising such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines (LCLs) and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal over 1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localise to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.

scholarly journals Review of: Metalloproteinase axes increase β-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3

2007 ◽  
Vol 10 (8) ◽  
Author(s):  
D. S. Salomon
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Target Genes ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Specific Effects ◽  
Primary Mouse ◽  
Ductal Elongation

Citation of original article:C. V. Hojilla, I. Kim, Z. Kassiri, J. E. Fat, H. Fang, R. Khokha. Journal of Cell Science 2007; 120(6): 1050–1060.Abstract of the original article:Multiple cancers exhibit mutations in β-catenin that lead to increased stability, altered localization or amplified activity. β-Catenin is situated at the junction between the cadherin-mediated cell adhesion and Wnt signaling pathways, and TIMP3 functions to alter β-catenin signaling. Here we demonstrate that primary mouse embryonic fibroblasts (MEFs) and mammary epithelial cells (MECs) deficient in Timp3 have increased β-catenin signaling. Functionally, the loss of TIMP3 exerted cell-type-specific effects, with Timp3−/− MEFs being more sensitive and Timp3−/− MECs more resistant to EGTA-induced cell detachment than the wild type. Timp3−/− MECs had higher dephosphorylated β-catenin levels and increased β-catenin transcriptional activity as measured by TCF/LEF-responsive reporter assays. Real-time PCR analysis of β-catenin target genes in MEFs and MECs showed no alteration in Myc, decreased Ccnd1 (cyclin D1) and increased Mmp7 mRNA levels upon loss of TIMP3, with the latter occurring only in epithelial cells. Recombinant TIMP3 and synthetic metalloproteinase inhibitors reverted the increase in dephosphorylated β-catenin, decrease in Ccnd1 gene expression and increase in Mmp7 gene expression. Physiologically, Timp3−/− mammary glands displayed accelerated mammary ductal elongation during pubertal morphogenesis. Gain-of-function studies using slow-release TIMP-containing pellets revealed distinct effects of individual TIMPs on ductal morphogenesis. Recombinant TIMP1, TIMP3 and TIMP4 inhibited ductal elongation whereas TIMP2 promoted this process.

198 PROGESTERONE, ESTROGEN (ER-α AND ER-β), AND OXYTOCIN RECEPTOR GENE EXPRESSION IN CANINE EMBRYOS

2013 ◽  
Vol 25 (1) ◽  
pp. 248
Author(s):  
A. A. P. Derussi ◽  
A. C. S. Castilho ◽  
R. W. A. Souza ◽  
R. Volpato ◽  
C. R. F. Guaitolini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Relative Abundance ◽  
Hormone Receptors ◽  
Target Genes ◽  
Receptor Gene ◽  
Rna Extraction ◽  
Amplification Efficiency ◽  
Mrna Levels ◽  
Lh Surge ◽  
Total Rna

The aim of this study was to compare the mRNA levels of hormone receptor for progesterone (PR), oestrogen α (ER-α), oestrogen β (ER-β), and oxytocin (OTR) in canine morulae and blastocysts. Ten healthy mature bitches were inseminated based on monitoring vaginal cytology and progesterone concentration. The first insemination was performed on Day 2 after the preovulatory LH surge (progesterone 4 ng mL–1), and the second was performed 48 h later. All females were submitted to ovariohysterectomy (OVH), and the oviduct as well the uterurs were flushed with PBS solution to obtain the embryos. The females were divided into two groups: Group A (n = 5), morulae were collected 8 days after the LH surge and Group B (n = 5), blastocysts were collected 12 days after the LH surge. The pools (n = 10) of embryos (5 embryos/pool) were stored in RNAlater® (Ambion, Life Technologies, USA) at –80°C. The samples were analysed together. The RNA later was removed used PBS calcium free and the total RNA extraction was performed using the Qiagen RNeasy micro-kit (Hildesheim, Germany). Before reverse-transcription (RT) reaction, the total RNA was treated with DNase I Amplification Grade (Invitrogen Life Technologies, Carlsbad, CA, USA). The gene expression of target genes was assessed by real-time RT-qPCR, using SuperScript III for RT and power SYBR Green PCR Master Mix (Applied Biosystems, USA) for cDNA for PCR. The primers for target genes were designed using the software Primer Express® (Applied Biosystems, USA). The gene expression of target genes was normalized by HPRT gene and the relative abundance of mRNA was determined by the ΔΔct method corrected by amplification efficiency using Pffafl’s equation. The means of mRNA relative abundance were compared by t-test. The PR mRNA expression only in blastocysts is similar to the results obtained by Hou et al. (1997) in rat embryos. It is believed that the absence of PR in the early stages of cleavage is due to the indirect action of progesterone by growth factors produced by the maternal reproductive tract (2). Apparently, ER-β action does not occur in the embryo canine phases analysed; however, the action of ER-α seems related to the deployment signal as seen by Hou et al. (1996) in rats. Similarly to findings in the literature, OTR expression decreased in canine embryonic development. This receptor was produced by blastocysts while present in the uterus, which may represent an incidental mechanism to the embryo control of endometrial receptivity, such as also to prevent the development of endometrial luteolytic mechanism. The variation in hormone receptors gene expression in canine embryos can be influencing the transition from morula to blastocyst. In addition, a hormonal influence on these structures can occur in different ways.

53 Pre-implantation exposure to bisphenol A and 4-tert-octylphenol result in disruption of calcium channels

2019 ◽  
Vol 31 (1) ◽  
pp. 152
Author(s):  
D. N. Tran ◽  
J.-H. Lee ◽  
Y.-M. Yoo ◽  
E.-M. Jung ◽  
C. Ahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bisphenol A ◽  
Calcium Transport ◽  
Oestrogen Receptor ◽  
Implantation Site ◽  
Vehicle Group ◽  
Mrna Levels ◽  
Implantation Failure ◽  
Transport Channel ◽  
Altered Expression

Miscarriage due to blastocyst implantation failure occurs in up to two-thirds of all miscarriage cases in humans. Calcium (Ca2+) has been shown to involve many cellular signal transduction pathways as well as regulation of cell adhesion, which is necessary for the physiology process of endometrial epithelial cell transformation and stromal cell decidualization during embryo implantation. Exposure to endocrine-disrupting chemicals (ED) can regulate the expression of genes associated with calcium transport in during pregnancy such as TRPV5, TRPV6, PMCA, and NCX1. Additionally, exposure to ED during early gestation results in disrupted intrauterine implantation, uterine receptive, leading to implantation failure. In this study, oestrogen (E2), bisphenol A (BPA), octylphenol (OP), and/or ICI 182,780 (oestrogen receptor antagonist, ICI) were injected subcutaneously from gestation Day 1 to gestation Day 3 post coitus. The number of implantation sites was significantly lower in the OP group, and no implantation site was observed in the E2 and ED+ICI groups. There were differences in the expression of calcium transient transport channel between maternal uterine and implantation. The level of TRPV6 and TRPV5 mRNA and protein was significantly increased by ED and/or ICI treatment in the uterus. The levels of TRPV5 and TRPV6 gene expression were significantly increased by ED with/without ICI treatment in the uterus. However, TRPV5 and TRPV6 gene expression was significantly lower in implantation site samples. The NCX1 and PMCA1 mRNA levels were significantly decreased by OP and BPA in the implantation site samples. Both mRNA and protein levels of MUC1 were markedly higher in all groups, except the BPA group when compared with the vehicle group in the uterus. The LIF and HOXA-10 mRNA were significantly low in E2; BPA+ICI; OP; and/or ICI in both the uterus and implantation site. Expression of the oestrogen receptor (ERa) and progesterone receptor (PR) was significantly lower in all groups except the BPA group when compared with the vehicle group. Taken together, E2, BPA, and OP disrupt the success of implantation through altered expression of calcium transport genes.

scholarly journals Treatment with PPARαAgonist Clofibrate Inhibits the Transcription and Activation of SREBPs and Reduces Triglyceride and Cholesterol Levels in Liver of Broiler Chickens

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Lijun Zhang ◽  
Chunyan Li ◽  
Fang Wang ◽  
Shenghua Zhou ◽  
Mingjun Shangguan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Broiler Chickens ◽  
Target Genes ◽  
Nuclear Protein ◽  
Mrna Level ◽  
Control Group ◽  
Mrna Levels ◽  
Protein Levels ◽  
Cholesterol Levels ◽  
Regulation Mechanisms

PPARαagonist clofibrate reduces cholesterol and fatty acid concentrations in rodent liver by an inhibition of SREBP-dependent gene expression. In present study we investigated the regulation mechanisms of the triglyceride- and cholesterol-lowering effect of the PPARαagonist clofibrate in broiler chickens. We observed that PPARαagonist clofibrate decreases the mRNA and protein levels of LXRαand the mRNA and both precursor and nuclear protein levels of SREBP1 and SREBP2 as well as the mRNA levels of the SREBP1 (FASNandGPAM) and SREBP2 (HMGCRandLDLR) target genes in the liver of treated broiler chickens compared to control group, whereas the mRNA level ofINSIG2, which inhibits SREBP activation, was increased in the liver of treated broiler chickens compared to control group. Taken together, the effects of PPARαagonist clofibrate on lipid metabolism in liver of broiler chickens involve inhibiting transcription and activation of SREBPs and SREBP-dependent lipogenic and cholesterologenic gene expression, thereby resulting in a reduction of the triglyceride and cholesterol levels in liver of broiler chickens.

Abstract 835: Downregulation Of Cardiomyocyte-enriched Micrornas Contributes To Altered Gene Expression In Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Sadakatsu Ikeda ◽  
Sek Won Kong ◽  
Jun Lu ◽  
Egbert Bisping ◽  
Natalya Bodyak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Calcium Signaling ◽  
Target Genes ◽  
Heart Function ◽  
Altered Expression ◽  
Regulate Gene Expression ◽  
False Discovery ◽  
Altered Gene ◽  
Calmodulin Signaling

Background: MicroRNAs (miRNAs) are a novel class of non-coding RNAs that regulate gene expression posttransciptionally. Altered miRNA expression has been implicated in diverse human diseases such as cancer. Accumulating evidence suggests the importance of miRNAs in the heart. However, the contribution of miRNAs to heart disease remains incompletely understood. Methods and Results: We measured the expression of 261 miRNAs in heart failure resulting from transgenic overexpression of calcineurin. 59 miRNAs were confidently detected in the heart, and 11 miRNAs belonging to 6 families (miR-1, -15, -30, -133, -195, -208) were downregulated compared to non-transgenic control (Welch’s t-test nominal p<0.05, false discovery rate <0.001). The results were validated by qRTPCR. There was no upregulated miRNA. Four of these miRNAs (miR-1, -30, -133, -208) were enriched in a purified cardiomyocyte preparation, compared to non-myocytes. Downregulation of these four miRNAs was reproduced in purified failing versus non-failing cardiomyocytes. This excluded artifactual downregulation from reduced myocyte fraction in failing hearts. The remaining two miRNAs (miR-15, and -195) were exclusively expressed in non-cardiomyocytes and did not changed in failing cardiomyocytes. Next, we used Affymetrix expression profiling to show that the predicted targets of these downregulated miRNAs were disproportionately upregulated compared to the entire transcriptome (Fisher’s exact p < 0.001). This suggests an association between downregulation of these miRNAs and upregulation of predicted target genes in heart failure. One particularly intriguing target of the predominant cardiac microRNA miR-1 is calmodulin, a key regulator of calcium signaling. We showed that calmodulin and downstream calmodulin signaling to NFAT is regulated by miR-1 in cultured cardiomyocytes. Conclusion: Our results indicate that altered expression of cardiomyocyte-enriched miRNAs may contribute to abnormal gene expression in heart failure. The regulation of calmodulin and calcium signaling by miR-1 suggests a mechanism by which miR-1 may regulate heart function.

siRNA Mediated Knockdown of the Chimeric Transcription Factor E2A-PBX1 Identifies Potential Target Genes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3179-3179
Author(s):  
Chun-Liang Chen ◽  
Harkness Connell ◽  
Ira Racoma ◽  
Brandi Regula ◽  
Katherine Foley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Pediatric Leukemia ◽  
Altered Expression ◽  
Qrt Pcr ◽  
Potential Target ◽  
Genome Wide ◽  
Genome Wide Gene Expression

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Several chromosomal translocations have prognostic significance and are used to classify patients for risk-directed therapy. The translocation t(1;19) which results in the fusion of TCF3 (E2A) and PBX1 genes occurs in 5% of pediatric ALL. E2A-PBX1 has been shown previously to have transcriptional activity. However, very little is known about what genes have altered expression in the presence of E2A-PBX1. To explore this question, we assessed genome wide gene expression after siRNA mediated knock down of E2A-PBX1. An E2A-PBX1 containing cell line (697) was transfected with E2A-PBX1 specific siRNA utilizing an Amaxa nucleofector2. Biologic replicates were performed by transfection of independent cultures. 70–80% reduction of E2A-PBX1 at mRNA and protein levels in 697 cells was reproducibly achieved using nucleofection and a combination of E2A-PBX1 specific siRNAs. Genome wide gene expression was assessed by Affymetrix U133 2.0 Plus arrays. Hybridizations were prepared and performed according to current Affymetrix protocols in the Functional Genomics Core at the Research Institute. Microarray data was normalized with RMA. Differentially expressed genes were selected using Significance Analysis of Microarrays (SAM). 78 probe sets demonstrated change in expression in E2A-PBX1 siRNA mediated knockdown relative to both mock transfection and nontargeting siRNA controls at a FDR of ≤ 5%. The 78 probe sets represent 49 known genes and 8 ESTs. Genes of specific interest upregulated by E2A-PBX1 include WNT-16, ANKS1B(EB-1), FAT, and RORB. Other investigators have previously cloned these genes by representational differential display from E2A-PBX1 expressing cell lines. We confirmed knockdown of these messages by E2A-PBX1 siRNA using qRT-PCR. Gene expression was calculated using the ΔΔCt method and normalization to ABL. Additionally, these genes are part of the E2A-PBX1 gene expression profile derived from primary pediatric leukemia samples previously published. [Ross, Blood 2003] An additional 34 candidate genes were further verified using qRT-PCR. The direction of change in gene expression correlated with microarray results in 30/34 genes evaluated. Other classes of genes upregulated by E2A-PBX1: kinases (FGFR2, MAP3K1), phosphtases (PPPIR14C), transcription factors (FOSL2, IRX2, EBF3, BMI1, BCL6), cell cycle-related genes (FBXW7, ETV5), Ras and Rho family genes (RAB8B). While B cell surface antigen expression (HLA-DRA, CD22) was decreased by E2A-PBX1. We have utilized siRNA to E2A-PBX1 to identify potential target genes of E2A-PBX1. This data suggests E2A-PBX1 can alter expression of a variety of classes of genes. Some of these genes may be potential targets for molecularly targeted therapy.

scholarly journals Foxa1 and Foxa2 Regulate α-Cell Differentiation, Glucagon Biosynthesis, and Secretion

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3781-3792 ◽  
Author(s):  
Mounia Heddad Masson ◽  
Caroline Poisson ◽  
Audrey Guérardel ◽  
Aline Mamin ◽  
Jacques Philippe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Target Genes ◽  
Adult Mouse ◽  
Glucagon Secretion ◽  
Mrna Levels ◽  
Forkhead Box ◽  
Interfering Rna

Abstract The Forkhead box A transcription factors are major regulators of glucose homeostasis. They show both distinct and redundant roles during pancreas development and in adult mouse β-cells. In vivo ablation studies have revealed critical implications of Foxa1 on glucagon biosynthesis and requirement of Foxa2 in α-cell terminal differentiation. In order to examine the respective role of these factors in mature α-cells, we used small interfering RNA (siRNA) directed against Foxa1 and Foxa2 in rat primary pancreatic α-cells and rodent α-cell lines leading to marked decreases in Foxa1 and Foxa2 mRNA levels and proteins. Both Foxa1 and Foxa2 control glucagon gene expression specifically through the G2 element. Although we found that Foxa2 controls the expression of the glucagon, MafB, Pou3f4, Pcsk2, Nkx2.2, Kir6.2, and Sur1 genes, Foxa1 only regulates glucagon gene expression. Interestingly, the Isl1 and Gipr genes were not controlled by either Foxa1 or Foxa2 alone but by their combination. Foxa1 and Foxa2 directly activate and bind the promoter region the Nkx2.2, Kir6.2 and Sur1, Gipr, Isl1, and Pou3f4 genes. We also demonstrated that glucagon secretion is affected by the combined effects of Foxa1 and Foxa2 but not by either one alone. Our results indicate that Foxa1 and Foxa2 control glucagon biosynthesis and secretion as well as α-cell differentiation with both common and unique target genes.

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