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Genome-wide chromatin accessibility and transcriptome profiling shows that minimal epigenome changes lead to coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice (ATAC-seq)

ABSTRACT: Genome-wide chromatin accessibility and transcriptome profiling shows that minimal epigenome changes lead to coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice (ATAC-seq)

PROVIDER: PRJNA428788 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6443050_1.fastq.gz	Fastqsanger.gz
	SRR6443050_2.fastq.gz	Fastqsanger.gz
	SRR6443051_1.fastq.gz	Fastqsanger.gz
	SRR6443051_2.fastq.gz	Fastqsanger.gz
	SRR6443052_1.fastq.gz	Fastqsanger.gz

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Genome-wide chromatin accessibility and transcriptome profiling shows that minimal epigenome changes lead to coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice (RNA-seq)

Project description:Danforth’s short tail (Sd) mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10,000 live births. Sd animals exhibit aberrant axial skeleton, urogenital, and gastrointestinal development similar to human caudal syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. Previous studies have shown that the Sd mutation results from an endogenous retroviral (ERV) insertion upstream of the Ptf1a gene causing its ectopic expression at E9. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue revealing localized changes in chromatin accessibility in Sd/Sd mutant embryos. Interestingly, chromatin changes were localized to a small genomic sequence overlapping a Ptf1a enhancer region, which is conserved in both mouse and humans. Furthermore, mRNA-Seq experiments revealed increased transcription of Ptf1a target genes and, importantly, the downregulation of the hedgehog pathway genes. Reduced Sonic hedgehog signaling (Shh) was confirmed by both in-situ hybridization and immunofluorescence experiments indicating that the Sd mutation may result, in part, from downregulated Shh signaling. Taken together these data indicate that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways. Thus it will be important to investigate how epigenome and transcriptome alterations result in hedgehog pathway disruption.

2018-10-31 | GSE108803 | GEO

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Project description:Genome-wide chromatin accessibility and transcriptome profiling shows that minimal epigenome changes lead to coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice

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2018-10-31 | GSE108804 | GEO

Proteomic profiling of the ciliary Hedgehog response reveals coordinated exit of GPR161 and PKA

Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

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Proteomic profiling of the ciliary Hedgehog response reveals coordinated exit of GPR161 and PKA

2021-04-07 | PXD024361 | Pride

Proteomic profiling of the ciliary Hedgehog response reveals coordinated exit of GPR161 and PKA

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Genome-wide chromatin accessibility and transcriptome profiling show minimal epigenome changes and coordinated transcriptional dysregulation of hedgehog signaling in Danforth's short tail mice.

Project description:Danforth's short tail (Sd) mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10 000 live births. Sd animals exhibit aberrant axial skeleton, urogenital and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, vertebral-anal-cardiac-tracheo-esophageal fistula-renal-limb (VACTERL) association and persistent cloaca. Previous studies have shown that the Sd mutation results from an endogenous retroviral (ERV) insertion upstream of the Ptf1a gene resulting in its ectopic expression at E9.5. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue, which revealed minimal changes in chromatin accessibility in Sd/Sd mutant embryos. Interestingly, chromatin changes were localized to a small interval adjacent to the Sd ERV insertion overlapping a known Ptf1a enhancer region, which is conserved in mice and humans. Furthermore, mRNA-seq experiments revealed increased transcription of Ptf1a target genes and, importantly, downregulation of hedgehog pathway genes. Reduced sonic hedgehog (SHH) signaling was confirmed by in situ hybridization and immunofluorescence suggesting that the Sd phenotype results, in part, from downregulated SHH signaling. Taken together, these data demonstrate substantial transcriptome changes in the Sd mouse, and indicate that the effect of the ERV insertion on Ptf1a expression may be mediated by increased chromatin accessibility at a conserved Ptf1a enhancer. We propose that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways.

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