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Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease

ABSTRACT: Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease

PROVIDER: PRJNA648084 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12304263_1.fastq.gz	Fastqsanger.gz
	SRR12304263_2.fastq.gz	Fastqsanger.gz
	SRR12304264_1.fastq.gz	Fastqsanger.gz
	SRR12304264_2.fastq.gz	Fastqsanger.gz
	SRR12304265_1.fastq.gz	Fastqsanger.gz

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Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease

Project description:It is widely recognized that the missing heritability of many human diseases is partially due to noncoding genetic variants, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals, and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multi-granular information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell-stage-specific regulatory roles three top novel regulatory elements on our list, respectively in the RET, RASGEF1A and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the affects the binding of the gliogenesis regulator NFIA, with a corresponding down-regulation of multiple genes in the same topologically associating domain.

2020-08-30 | GSE154972 | GEO

Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease.

Project description:It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage-specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.

| S-EPMC7605255 | biostudies-literature

Single-cell RNA sequencing of small intestine neurons in Hirschsprung disease mice

Project description:This study was undertaken to identify gene expression changes in enteric neurons of Hirschsprung disease mice. Methods: We performed single-cell RNA sequencing of enteric nervous system cells isolated from the small intestine of Ednrb-knockout mice at age P14. Results: Through comparisons with published datasets of WT small intestine enteric neurons, we identify a missing neuronal population in the ganglionated small intestine of Hirschsprung disease mice. Conclusion: Single-cell RNA sequencing permits identification of cellular perturbations in Hirschsprung disease models.

2022-08-24 | GSE199683 | GEO

Detection of gene cis-regulatory element perturbations in single-cell transcriptomes

Project description:Detection of gene cis-regulatory element perturbations in single-cell transcriptomes

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Assessment Of Long Noncoding RNA CCAT1 In Colorectal Cancer Patients

Project description:1. Evaluate the diagnostic value of long noncoding RNA (CCAT1) expression by RT-PCR in peripheral blood in colorectal cancer patients versus normal healthy control personal. 2. Evaluate the clinical utility of detecting long noncoding RNA (CCAT1) expression in diagnosis of colorectal cancer patients & its relation to tumor staging. 3. Evaluate the clinical utility of detecting long noncoding RNA (CCAT1) expression in precancerous colorectal diseases. 4. Compare long noncoding RNA (CCAT1) expression with traditional marker; carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9) in diagnosis of colorectal cancer.

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An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation (CRISPRi screen) [ACHN]

Project description:Cancer cells frequently upregulate ribosome production to support tumorigenesis. While small nucleolar RNAs (snoRNAs) are critical for ribosome biogenesis, the roles of other classes of noncoding RNAs in this process remain largely unknown. Here we performed CRISPR screens to identify essential long noncoding RNAs (lncRNAs) in renal cell carcinoma (RCC) cells. This revealed that an alternatively-spliced isoform of lncRNA Colorectal Neoplasia Differentially Expressed containing an ultraconserved element (UCE), referred to as CRNDEUCE, is required for RCC cell proliferation. CRNDEUCE localizes to the nucleolus and promotes 60S ribosomal subunit biogenesis. The UCE of CRNDE functions as an unprocessed C/D box snoRNA that directly interacts with ribosomal RNA precursors. This facilitates delivery of eIF6, a key 60S biogenesis factor, which binds to CRNDEUCE through a sequence element adjacent to the UCE. These findings highlight the functional versatility of snoRNA sequences and expand the known mechanisms through which noncoding RNAs orchestrate ribosome biogenesis.

2025-03-24 | GSE270849 | GEO

An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation (CRISPRi screen) [A-498]

2025-03-24 | GSE270848 | GEO

An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation (CRISPRi screen) [786-O]

2025-03-24 | GSE270847 | GEO

CRISPRai Regulatory Element Screens [Series 2]

Project description:We develop a system for bidirectional epigenetic editing (CRISPRai), in which orthogonal activating (CRISPRa) and repressive (CRISPRi) perturbations are applied simultaneously to multiple loci the same cell. We perform CRISPR gRNA enrichment screens to investigate pairwise CRISPRai perturbations of enhancers and the promoter of IL2 and IFNG genes in order to investigate enhancer-enhancer and enhancer-promoter interactions and regulatory element heirarchies.

2024-03-14 | GSE220975 | GEO

Alternative splicing of a transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification

Project description:The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The CARMEN locus, which is known to dictate specification towards the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a diversity of alternatively spliced lncRNAs. Here, we identify one of these isoforms, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively-spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced. These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA.

2022-08-01 | GSE199930 | GEO

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