Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Conditionally Pathogenic Genetic Variants of a Hematopoietic Disease-Suppressing Enhancer

ABSTRACT: Conditionally Pathogenic Genetic Variants of a Hematopoietic Disease-Suppressing Enhancer

PROVIDER: PRJNA744950 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR15076585_1.fastq.gz	Fastqsanger.gz
	SRR15076585_2.fastq.gz	Fastqsanger.gz
	SRR15076586_1.fastq.gz	Fastqsanger.gz
	SRR15076586_2.fastq.gz	Fastqsanger.gz
	SRR15076587_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 20

Similar Datasets

Conditionally Pathogenic Genetic Variants of a Hematopoietic Disease-Suppressing Enhancer

Project description:Human genetic variants are classified based on potential pathogenicity to guide clinical decisions. However, mechanistic uncertainties often preclude definitive categorization. Germline coding and enhancer variants within the hematopoietic regulator GATA2 create a bone marrow failure and leukemia predisposition. The conserved murine enhancer promotes hematopoietic stem cell (HSC) genesis, and a single-nucleotide human variant in an Ets motif attenuates chemotherapy-induced hematopoietic regeneration. We describe “conditionally pathogenic” (CP) enhancer motif variants that differentially impact hematopoietic development and regeneration. The Ets motif variant functioned cell-autonomously in hematopoietic cells to disrupt hematopoiesis. Since an epigenetically-silenced normal allele can exacerbate phenotypes of a pathogenic heterozygous variant, we engineered a bone marrow failure model harboring the Ets motif variant and a severe enhancer mutation on the second allele. Despite normal developmental hematopoiesis, regeneration in response to chemotherapy, inflammation, and a therapeutic HSC mobilizer was compromised. The CP paradigm informs mechanisms underlying phenotypic plasticity and clinical genetics.

2021-12-15 | GSE179790 | GEO

Conditionally pathogenic genetic variants of a hematopoietic disease-suppressing enhancer.

Project description:Human genetic variants are classified on the basis of potential pathogenicity to guide clinical decisions. However, mechanistic uncertainties often preclude definitive categorization. Germline coding and enhancer variants within the hematopoietic regulator GATA2 create a bone marrow failure and leukemia predisposition. The conserved murine enhancer promotes hematopoietic stem cell (HSC) genesis, and a single-nucleotide human variant in an Ets motif attenuates chemotherapy-induced hematopoietic regeneration. We describe “conditionally pathogenic” (CP) enhancer motif variants that differentially affect hematopoietic development and regeneration. The Ets motif variant functioned autonomously in hematopoietic cells to disrupt hematopoiesis. Because an epigenetically silenced normal allele can exacerbate phenotypes of a pathogenic heterozygous variant, we engineered a bone marrow failure model harboring the Ets motif variant and a severe enhancer mutation on the second allele. Despite normal developmental hematopoiesis, regeneration in response to chemotherapy, inflammation, and a therapeutic HSC mobilizer was compromised. The CP paradigm informs mechanisms underlying phenotypic plasticity and clinical genetics.

| S-EPMC8664263 | biostudies-literature

Tristetraprolin prevents gastric metaplasia by suppressing pathogenic inflammation

Project description:Tristetraprolin prevents gastric metaplasia by suppressing pathogenic inflammation

| PRJNA690083 | ENA

Investigating DNA methylation in individuals with pathogenic variants in SCN1A

Project description:SCN1A, encoding the sodium channel protein type 1 alpha subunit, is the most implicated gene in epilepsy. Pathogenic loss-of-function variants that result in SCN1A haploinsufficiency cause the most common DEE, known as Dravet syndrome (DS). Pathogenic gain-of-function variants have been found to cause a more severe, early-onset epilepsy syndrome that is distinct from DS. Here, we investigated DNA methylation patterns in these individuals with SCN1A variants.

2024-10-25 | GSE280241 | GEO

Integrative Analysis of Pathogenic Structural Variants in Leukemia Genomes

Project description:Pathogenic Structural Variants in Leukemia Genomes

| PRJEB50975 | ENA

Enhancer Sequence Variants and Transcription Factor Deregulation Synergize to Construct Pathogenic Regulatory Circuits in B Cell Lymphoma (RNA-Seq)

Project description:Most B cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC-B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions transcriptional circuits from normal GC-B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression is deregulated in FL, target commandeered versus decommissioned REs. Our approach reveals two distinct subtypes of low-grade FL, whose pathogenic circuitries resemble GC-B or activated B cells. Remarkably, FL-altered enhancers also are enriched for sequence variants, including somatic mutations, which disrupt transcription factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC-B transformation. Expression profiles of follicular lymphoma, centrocyte and peripheral blood B cells were generated by deep sequencing, using Illumina Hi-Seq 2000.

2015-01-15 | E-GEOD-62241 | biostudies-arrayexpress

Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses

Project description:Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses

| PRJNA506378 | ENA

Classifying pathogenic variants in amyloid beta using intramolecular genetic interaction profiling

Project description:Changes in the amino acid sequences of proteins cause thousands of human genetic diseases. However, only a subset of variants in any protein is typically pathogenic, with variants having a diversity of molecular consequences. Determining which of the thousands of possible variants in any protein have similar molecular effects is very challenging, but crucial for identifying pathogenic variants, determining disease mechanisms, understanding clinical phenotypic variation, and developing targeted therapeutics. Here we present a general method to classify variants by their molecular effects that we term intramolecular genetic interaction profiling. The approach relies on the principle that variants with similar molecular consequences have similar genetic interactions with other variants in the same protein. These intramolecular genetic interactions are straightforward to quantify for any protein with a selectable function. We apply intramolecular genetic interaction profiling to amyloid beta, the protein that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). Genetic interactions identify two classes of gain-of-function variants, with all known familial Alzheimer’s disease variants having very similar genetic interaction profiles, consistent with a common gain-of-function mechanism leading to pathology. We believe that intramolecular genetic interaction profiling is a powerful approach for classifying variants in disease genes that will empower rare variant association studies and the discovery of disease mechanisms.

2023-11-15 | GSE247583 | GEO

Enhancer Sequence Variants and Transcription Factor Deregulation Synergize to Construct Pathogenic Regulatory Circuits in B Cell Lymphoma (ChIP-Seq, FAIRE-Seq)

Project description:Most B cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC-B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions transcriptional circuits from normal GC-B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression is deregulated in FL, target commandeered versus decommissioned REs. Our approach reveals two distinct subtypes of low-grade FL, whose pathogenic circuitries resemble GC-B or activated B cells. Remarkably, FL-altered enhancers also are enriched for sequence variants, including somatic mutations, which disrupt transcription factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC-B transformation. Molecular profiling of follicular lymphoma, resting peripheral blood and tonsillar B cells using Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) and chromatin immunoprecipitation (H3ac and H3K27ac).

2015-01-15 | E-GEOD-62245 | biostudies-arrayexpress

High frequency of pathogenic germline variants in genes associated with homologous recombination repair in patients with advanced solid cancers

Project description:We identified pathogenic and likely pathogenic variants in 17.8% of the patients within a wide range of cancer types. In particular, mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. In total, 22 BRCA1 and BRCA2 germline variant were identified in 12 different cancer types, of which 10 (45%) variants were not previously identified in these patients. Pathogenic germline variants were predominantly found in DNA repair pathways; approximately half of the variants were within genes involved in homologous recombination repair. Loss of heterozygosity and somatic second hits were identified in several of these genes, supporting possible causality for cancer development. A potential treatment target based on pathogenic germline variant could be suggested in 25 patients (4%).

2019-05-11 | GSE131027 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data