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Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [4C]

ABSTRACT: Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [4C]

PROVIDER: PRJNA794845 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17453434.fastq.gz	Fastqsanger.gz
	SRR17453435.fastq.gz	Fastqsanger.gz
	SRR17453436.fastq.gz	Fastqsanger.gz
	SRR17453437.fastq.gz	Fastqsanger.gz
	SRR17453438.fastq.gz	Fastqsanger.gz

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Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

Project description:Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

| PRJNA794841 | ENA

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [4C]

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

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]

Project description:Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]

| PRJNA794847 | ENA

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]

2022-02-23 | GSE193113 | GEO

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism.

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

Pathogenicity of genomic duplications is determined by formation of novel chromatin domains (neo-TADs) (4C-seq)

Project description:Genome-scale methods have identified subchromosomal structures so-called topologically associated domains (TADs) that subdivide the genome into discrete regulatory units, establish with their target genes. By re-engineering human duplications at the SOX9 locus in mice combined with 4C-seq and Capture Hi-C experiments, we show that genomic duplications can result in the formation of novel chromatin domains (neo-TADs) and that this process determines their molecular pathology.

2016-10-06 | GSE78067 | GEO

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-02-23 | GSE193114 | GEO

Pathogenicity of genomic duplications is determined by formation of novel chromatin domains (neo-TADs) (RNA-seq)

2016-10-06 | GSE78105 | GEO

Pathogenicity of genomic duplications is determined by formation of novel chromatin domains (neo-TADs) [Hi-C]

2016-10-06 | GSE78072 | GEO

Pathogenicity of genomic duplications is determined by formation of novel chromatin domains (neo-TADs) (4C-seq)

Project description:Pathogenicity of genomic duplications is determined by formation of novel chromatin domains (neo-TADs) (4C-seq)

| PRJNA312529 | ENA