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A complementary study pipeline unravels novel players in the pathoetiology of Hirschsprung's disease

ABSTRACT: A complementary study pipeline unravels novel players in the pathoetiology of Hirschsprung's disease

PROVIDER: PRJNA603668 | ENA |

REPOSITORIES: ENA

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A complementary study pipeline unravels novel players in the pathoetiology of Hirschsprung's disease

Project description:Purpose: Hirschsprung’s disease (HSCR, OMIM 142623) represents one of the main causes of neonatal intestinal obstruction. It is caused by dysfunction of neural crest cells (NCCs) and their progeny during development of the enteric nervous system (ENS). HSCR is considered a multifactorial disorder, however, associated risk genes only account for a minority of cases. Consequently, defining disease-relevant variants is still a demanding task. Methods: To reduce the number of candidate genes identified by Whole Exome Sequencing (WES) and to examine their disease-causing relevance, we established a complementary study pipeline including transcriptome data of murine embryonic ENS-relevant tissues, literature and database searches, in silico network analyses as well as functional assays using genome-edited candidate-specific cell clones. Results: Applying this strategy on a pilot set of two HSCR patients and their non-affected parents led to the identification of four novel HSCR candidate genes: ATP7A, SREBF1, ABCD1 and PIAS2. This candidate gene selection was corroborated by the discovery of further rare variants in additional HSCR cases. Moreover, expression analyses revealed that all four genes are expressed in embryonic murine gastrointestinal tissues. Functional analyses using candidate gene-specific, neuronal-like CRISPR/Cas9-edited knockout cell clones demonstrated impaired differentiation, proliferation and/or cell survival capacity. Conclusions: Taken together, the presented study pipeline was proven to be suitable for the selection and validation of candidate genes as well as to gain insight into underlying pathomechanisms of HSCR.

2020-10-12 | GSE144442 | GEO

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.

Project description:Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.

| S-EPMC7643938 | biostudies-literature

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A new pipeline SPICE identifies novel JUN-IKZF1 composite elements

Project description:Transcription factor partners can cooperatively bind to DNA composite elements to augment gene transcription. Here, we report a novel protein-DNA binding screening pipeline, termed Spacing Preference Identification of Composite Elements (SPICE), that can systematically predict protein binding partners and DNA motif spacing preferences. SPICE de novo predicted known composite elements, including AP1-IRF composite elements (AICE) and STAT5 tetramers, and also predicted a range of novel binding partners, including JUN-IKZF1 composite elements. We confirmed cooperative binding of JUN and IKZF1 to an upstream conserved noncoding region, CNS9, in the human IL10 gene, that contains a non-canonical IKZF1 site, and the activity of an IL10-luciferase reporter construct depended on both this site and the AP1 binding site within this composite element in primary B and T cells. Our findings reveal an unappreciated global association of IKZF1 and AP1, and establish SPICE as a valuable new pipeline for predicting novel transcription binding complexes.

2023-11-05 | GSE230035 | GEO

RNA-seq dynamic transcriptomic pipeline

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Project description:A new pipeline SPICE identifies novel JUN-IKZF1 composite elements

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IS-Seq: a novel bioinformatics pipeline for integration sites analysis

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