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Non-telomeric role for Rap1 in regulating metabolism and protecting against obesity

ABSTRACT: The mammalian telomere-binding protein Rap1 was found to have additional non-telomeric functions, acting as a transcriptional cofactor and a regulator of the NF-kB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo, and report on its unanticipated role in metabolic regulation and body weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function. In addition, using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, and at other interstitial loci. We have utilized microarrays to outline gene expression changes resulting from Rap1-deficiency when compared to the wild-type controls. Total RNA was isolated from the liver and intra-abdominal white adipose tissue of 3 female Rap1 deficient mice and 3 control littermates at 6-8 weeks of age. Rap1 deficient mouse embryonic fibroblasts (MEF) were isolated from 13.5 day embryos, immortalized with SV40LgT, and stably infected with vector, Rap1-wildtype, or Rap1 carrying an isoleucine to arginine mutation at amino acid 312. Total RNA was extracted from MEFs following a similar protocol. The samples were labeled, hybridized, and scanned using standard protocols by the Core Facility at NYU Langone Medical Center on Affymetrix GeneChip Mouse Genome 430 2.0 Arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Frank Yeung

PROVIDER: E-GEOD-46209 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Non-telomeric role for Rap1 in regulating metabolism and protecting against obesity

Project description:The mammalian telomere-binding protein Rap1 was found to have additional non-telomeric functions, acting as a transcriptional cofactor and a regulator of the NF-kB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo, and report on its unanticipated role in metabolic regulation and body weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function. In addition, using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, and at other interstitial loci. We have utilized microarrays to outline gene expression changes resulting from Rap1-deficiency when compared to the wild-type controls.

2013-06-01 | GSE46209 | GEO

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (old mouse liver)

Project description:RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres. Unlike other shelterins, however, RAP1 is not essential for preventing telomere fusions. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the non-telomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knock-out mouse model. Unexpectedly, these mice presented an early onset of obesity, which was particularly severe in females and was aggravated under a high-fat diet. Rap1-deficient mice showed abnormal accumulation of fat in abdominal depots and developed signs of type II diabetes and metabolic syndrome, including hepatic steatosis and high fasting plasma levels of insulin, glucose, cholesterol, and alanine transaminase. Gene expression analyses of the liver and visceral white fat from Rap1-deficient mice before the onset of obesity indicated deregulation of key metabolic transcriptional programs including fatty acid metabolism, PPARa signalling and glucose metabolism. Transcriptome and Western blotting analyses in liver further identified Ppara and Pgc1a and their target genes as the key metabolic pathways affected by Rap1 deletion. Finally, we show here that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings underscore an unprecedented role for a telomere-binding protein in the regulation of metabolism. 2 condition experiment: WT versus Rap1 knockout. Tissue: liver. 3 biological replicates per genotype. Mice were 30 weeks old.

2013-06-21 | E-GEOD-43173 | biostudies-arrayexpress

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (young mouse liver)

Project description:RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres. Unlike other shelterins, however, RAP1 is not essential for preventing telomere fusions. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the non-telomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knock-out mouse model. Unexpectedly, these mice presented an early onset of obesity, which was particularly severe in females and was aggravated under a high-fat diet. Rap1-deficient mice showed abnormal accumulation of fat in abdominal depots and developed signs of type II diabetes and metabolic syndrome, including hepatic steatosis and high fasting plasma levels of insulin, glucose, cholesterol, and alanine transaminase. Gene expression analyses of the liver and visceral white fat from Rap1-deficient mice before the onset of obesity indicated deregulation of key metabolic transcriptional programs including fatty acid metabolism, PPARa signalling and glucose metabolism. Transcriptome and Western blotting analyses in liver further identified Ppara and Pgc1a and their target genes as the key metabolic pathways affected by Rap1 deletion. Finally, we show here that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings underscore an unprecedented role for a telomere-binding protein in the regulation of metabolism. 2 condition experiment: WT versus Rap1 knockout. Tissue: liver. 4 biological replicates per genotype. Mice were 10 weeks old.

2013-06-21 | E-GEOD-43171 | biostudies-arrayexpress

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (young mouse white fat)

Project description:RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres. Unlike other shelterins, however, RAP1 is not essential for preventing telomere fusions. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the non-telomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knock-out mouse model. Unexpectedly, these mice presented an early onset of obesity, which was particularly severe in females and was aggravated under a high-fat diet. Rap1-deficient mice showed abnormal accumulation of fat in abdominal depots and developed signs of type II diabetes and metabolic syndrome, including hepatic steatosis and high fasting plasma levels of insulin, glucose, cholesterol, and alanine transaminase. Gene expression analyses of the liver and visceral white fat from Rap1-deficient mice before the onset of obesity indicated deregulation of key metabolic transcriptional programs including fatty acid metabolism, PPARa signalling and glucose metabolism. Transcriptome and Western blotting analyses in liver further identified Ppara and Pgc1a and their target genes as the key metabolic pathways affected by Rap1 deletion. Finally, we show here that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings underscore an unprecedented role for a telomere-binding protein in the regulation of metabolism. 2 condition experiment: WT versus Rap1 knockout. Tissue: white gonadal fat. 4 biological replicates per genotype. Mice were 10 weeks old.

2013-06-21 | E-GEOD-43172 | biostudies-arrayexpress

ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

2023-10-21 | PXD043084 | Pride

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (old mouse liver)

2013-06-21 | GSE43173 | GEO

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (young mouse liver)

2013-06-21 | GSE43171 | GEO

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (young mouse white fat)

2013-06-21 | GSE43172 | GEO

ZBTB10 binds the telomeric variant repeat TTGGGG and interacts with TRF2

Project description:Telomeres are the ends of linear chromosomes and together with the shelterin complex present an essential feature for genome integrity. Vertebrate telomeres usually consist of hexameric TTAGGG repeats, however, in cells that use the alternative lengthening of telomeres (ALT) mechanism, variant repeat sequences are interspersed throughout telomeres. Previously, it was shown that NR2C/F transcription factors bind to TCAGGG variant repeats and contribute to telomere maintenance in ALT cells. While specific binders to other variant repeat sequences have been lacking to date, we here identify ZBTB10 as the first TTGGGG-binding protein and demonstrate direct binding via the two zinc fingers with affinity in the nanomolar range. Concomitantly, ZBTB10 co-localizes with a subset of telomeres in ALT-positive U2OS cells and interacts with TRF2/RAP1 via the N-terminal region of TRF2. Our data establishes ZBTB10 as a novel variant repeat-specific binding protein at ALT telomeres.

2018-12-17 | PXD010672 | Pride

Genome-wide maps of RAP1 binding sites.

Project description:By performing chromatin immunoprecipitation coupled with ultra-high-throughput sequencing (ChIP-seq), we find that RAP1 binds to telomeres as well as to extra-telomeric sites through the (TTAGGG)2 consensus motif. Extra-telomeric RAP1 binding sites are particularly abundant at subtelomeric regions, and this is in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. Significantly, more than 70% of extratelomeric RAP1 binding sites are located in the vicinity of known genes and about 40% of the genes deregulated in Rap1-null cells contain binding sites for RAP1, suggesting a role of RAP1 in transcriptional control.

2010-07-10 | GSE20867 | GEO

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