Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA794847 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17454413_1.fastq.gz | Fastqsanger.gz | |||
| SRR17454413_2.fastq.gz | Fastqsanger.gz | |||
| SRR17454414.fastq.gz | Fastqsanger.gz | |||
| SRR17454415.fastq.gz | Fastqsanger.gz | |||
| SRR17454416_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 10 |
Similar Datasets
Project description:Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism
| PRJNA794841 | ENA
Project description:Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [4C]
| PRJNA794845 | ENA
Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, we showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Then, we showed that the duplications in multiple patients led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary.
2022-02-23 | GSE193112 | GEO
Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, we showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Then, we showed that the duplications in multiple patients led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary.
2022-02-23 | GSE193113 | GEO
Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
| S-EPMC9069129 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-23 | GSE193114 | GEO
Project description:While nucleotide-resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact on phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing we constructed fine-resolution, species-specific structural variation and segmental duplication maps for five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, comprising thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques. Non-allelic homologous recombination, linked with genomic architecture, primarily shaped the genomes of great apes resulting in different SV formation mechanism landscapes across species, with distinct functional consequences. Transcriptome analyses across nonhuman primates and humans revealed significant effects of species-specific gene duplications on gene expression, with these effects displaying remarkable diversity in direction and magnitude. Thirteen inter-species gene duplications coincided with the species-specific gain of expression in a new tissue, implicating these duplications in function acquisition. Agilent arrays were custom designed for probes to be relatively evenly spaced across the reference genomes of chimpanzee, orang-utan, and rhesus macaque. For each species 9 one million probe arrays were used to cover the autosomes and a single 400k probe array was used for the sex chromosomes.
2013-08-10 | E-GEOD-45741 | biostudies-arrayexpress
Project description:Interpreting the genomic and phenotypic consequences of copy number variation (CNV) is essential to understand the etiology of genetic disorders. Whereas deletion CNVs obviously lead to haploinsufficiency, duplications may cause disease through triplosensitivity, gene disruption, or gene fusion at breakpoints. The mutational spectrum of duplications has been studied at certain loci and in some cases these copy number gains are complex chromosome rearrangements involving triplications and/or inversions. However, the organization of clinically relevant duplications throughout the genome has not been investigated on a large scale. Here, we fine mapped 184 germline duplications (14.7 kb-25.3 Mb; median 532 kb) ascertained from individuals referred for diagnostic cytogenetics testing. We performed next-generation sequencing (NGS) and whole-genome sequencing (WGS) to sequence 130 breakpoints from 112 subjects with 119 CNVs and found that most (83%) were tandem duplications in direct orientation. The remainder were triplications embedded within duplications (8.4%), adjacent duplications (4.2%), insertional translocations (2.5%), or other complex rearrangements (1.7%). In addition, we predicted six in-frame fusion genes at sequenced duplication breakpoints. Four gene fusions were formed by tandem duplications, one by two interconnected duplications, and one by duplication inserted at another locus. These novel fusion genes could be related to clinical phenotypes and warrant further study. Though most duplications are positioned head-to-tail adjacent to the original locus, those that are inverted, triplicated, or inserted can disrupt or fuse genes in a manner that may not be predicted by conventional copy number analysis. Thus, interpreting the genetic consequences of duplication CNVs requires breakpoint-level analysis.
2014-10-25 | GSE62657 | GEO
Project description:While nucleotide-resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact on phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing we constructed fine-resolution, species-specific structural variation and segmental duplication maps for five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, comprising thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques. Non-allelic homologous recombination, linked with genomic architecture, primarily shaped the genomes of great apes resulting in different SV formation mechanism landscapes across species, with distinct functional consequences. Transcriptome analyses across nonhuman primates and humans revealed significant effects of species-specific gene duplications on gene expression, with these effects displaying remarkable diversity in direction and magnitude. Thirteen inter-species gene duplications coincided with the species-specific gain of expression in a new tissue, implicating these duplications in function acquisition.
2013-08-10 | GSE45741 | GEO
Project description:This study centered on using a custom made Nimblegen aCGH chip that targeted all segmental duplications in the canine genome to identify associated CNVs. A total of 19 hybridizations were performed in a panel of diverse dogs and a single wolf. Using computational approaches all segmental duplications were identified in the canFam2 genome of the dog. A custom aCGH chip was then built that densely interrogated these segmental duplications for CNVs in a panel of diverse dog breeds and a single wolf.
2010-05-17 | E-GEOD-13266 | biostudies-arrayexpress