RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function
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ABSTRACT:
PROVIDER: PRJNA980693 | ENA |
REPOSITORIES: ENA
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Project description:We performed bulk RNA-seq analysis for CRISPR-Cpf1 mutated H1 cells that were differentiated into pancreatic cells. Homozygous mutant was compared to control cells (RFX6-/- vs RFX6+/+) at stage 3 (PF) and stage 5 (EP), and heterozygous mutant was compared to control cells (RFX6-/+ vs RFX6+/+) at stage 7 (SC-islets).
2024-04-11 | GSE234289 | GEO
Project description:Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes but the underlying mechanisms remain unclear. Here we show that Rfx6, whose mutation leads to neonatal diabetes in man, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing and to defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway including GLucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2 channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of M-bM-^@M-^\disallowedM-bM-^@M-^] genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in man. Two ChIP-Seq experiments have been performed : 1) anti-HA ChIP-Seq on 3HA-Rfx6 transfected Min6b1 cells and 2) anti-HA ChIP-Seq on Min6b1 cells
2014-12-11 | E-GEOD-62844 | biostudies-arrayexpress
Project description:Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes but the underlying mechanisms remain unclear. Here we show that Rfx6, whose mutation leads to neonatal diabetes in man, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing and to defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway including GLucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2 channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in man.
2014-12-11 | GSE62844 | GEO
Project description:Hyperuricemia Predisposes to the Onset of Diabetes
| PRJNA596990 | ENA
Project description:DNMT3A (which encodes a de novo DNA methyltransferase) is one of the most frequently mutated genes in AML genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins, which could either have dominant negative activities, or cause loss-of-function and haploinsufficiency. We demonstrate that three of these mutants produce truncated, inactive proteins that do not dimerize with wild-type DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation: unmanipulated mice developed myeloid skewing over time, and their stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice spontaneously developed transplantable myeloid malignancies after a long latent period, and three of 12 tumors tested had cooperating mutations in the Ras- MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for DNMT3A alters hematopoiesis, and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.
2017-08-01 | GSE100702 | GEO
Project description:Recently a new neonatal diabetes syndrome, Mitchell-Riley syndrome, was discovered. To identify the genetic cause of the syndrome homozygosity mapping was used, several chromosomal regions were linked to Mitchell-Riley syndrome. In situ hybridization of genes from one such region using model organism Xenopus laevis identified RFX6 as a potential candidate gene; mutant forms of RFX6 were subsequently found in Mitchell-Riley patients. Analysis of the expression pattern of RFX6 in Xenopus development shows it is expressed broadly in the endoderm early in development, and later RFX6 becomes restricted to the endocrine cells of the gut and pancreas. Morpholino knockdown of RFX6 in Xenopus caused a loss of pancreas marker gene expression. Injection of exogenous wild type RFX6 rescued the morpholino phenotype in Xenopus tadpoles. Attempts to rescue the loss-of-function phenotype using mutant forms of RFX6 found in Mitchell-Riley patients were unsuccessful suggesting the changes lead to loss-of-function and could be the cause of Mitchell-Riley syndrome. Microarray analysis of gene expression in knockdown tissue suggested a downregulation in marker genes for lung, stomach and heart, ambiguous results for the liver, and an upregulation in kidney marker gene expression. RT-PCR and in situ hybridization confirms a loss of lung, stomach and heart gene expression, no change in liver marker hex and an upregulation in kidney marker KcnJ1. The fact that the morpholino phenotype affects multiple organs suggests that RFX6 has a broad role early in endoderm development.
2011-01-24 | GSE23642 | GEO
Project description:Recently a new neonatal diabetes syndrome, Mitchell-Riley syndrome, was discovered. To identify the genetic cause of the syndrome homozygosity mapping was used, several chromosomal regions were linked to Mitchell-Riley syndrome. In situ hybridization of genes from one such region using model organism Xenopus laevis identified RFX6 as a potential candidate gene; mutant forms of RFX6 were subsequently found in Mitchell-Riley patients. Analysis of the expression pattern of RFX6 in Xenopus development shows it is expressed broadly in the endoderm early in development, and later RFX6 becomes restricted to the endocrine cells of the gut and pancreas. Morpholino knockdown of RFX6 in Xenopus caused a loss of pancreas marker gene expression. Injection of exogenous wild type RFX6 rescued the morpholino phenotype in Xenopus tadpoles. Attempts to rescue the loss-of-function phenotype using mutant forms of RFX6 found in Mitchell-Riley patients were unsuccessful suggesting the changes lead to loss-of-function and could be the cause of Mitchell-Riley syndrome. Microarray analysis of gene expression in knockdown tissue suggested a downregulation in marker genes for lung, stomach and heart, ambiguous results for the liver, and an upregulation in kidney marker gene expression. RT-PCR and in situ hybridization confirms a loss of lung, stomach and heart gene expression, no change in liver marker hex and an upregulation in kidney marker KcnJ1. The fact that the morpholino phenotype affects multiple organs suggests that RFX6 has a broad role early in endoderm development. Xenopus laevis embryos were injected with morpholinos, either mismatch control (MM) or RFX6 start site (MO1), at the 8-cell stage. The foreguts of the resulting tadpoles were dissected at 3 different stages of development, NF30, NF40 and NF44.
2011-01-24 | E-GEOD-23642 | biostudies-arrayexpress
Project description:The gastrointestinal (GI) tract consists of highly specialized organs from the proximal esophagus to the distal colon, each with unique functions. Rare congenital malformations of the GI tract, including organ atresia, agenesis or mispatterning are linked to gene mutations although the molecular basis of these malformations has been poorly studied due to lack of model systems to study human development. We identified a patient with compound heterozygous mutations in the transcription factor RFX6 with pancreatic agenesis as previously described. In addition, the patient had duodenal mal-rotation and atresia suggesting that establishment of the proximal small intestine was impaired in these patients. To identify the molecular basis of the intestinal malformation we generated induced pluripotent stem cell lines from this patient, and derived human intestinal organoid (HIOs) to identify how mutations in RFX6 impact intestinal patterning and function. We identified that the duodenal identity of HIOs and patient tissues had adopted a more distal small intestinal signature, including expression of SATB2, normally expressed in the ileum and colon. CRISPR-mediated correction of RFX6 restored duodenal identity, including expression of PDX1, which is required for duodenal development. Using transcriptomic approaches in HIOs and Xenopus embryos we identified that PDX1 is a downstream transcriptional target of RFX6 and that PDX1 expression in a RFX6 mutant background was sufficient to rescue duodenal identity. However, RFX6 had additional transcriptional activities that were separate from PDX1, in particular to regulate multiple components of signaling pathways that are critical for establishing early regional identity in the GI tract including WNT, HH, and BMP pathways. In summary, we have identified that RFX6 is one of the most upstream regulators early intestinal patterning in vertebrates and that it acts by regulating key transcriptional and signaling pathways.
2024-03-19 | GSE245474 | GEO
Project description:Background: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumor and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation (ChIP), untargeted metabolome profiling, and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of PGAM1 and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
2023-12-20 | GSE248063 | GEO
Project description:Background: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumor and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation (ChIP), untargeted metabolome profiling, and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of PGAM1 and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
2023-12-20 | GSE248062 | GEO