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An erythroid-specific enhancer of ATP2B4 mediates red blood cell hydration and malaria susceptibility [genotype]

ABSTRACT: Few genotype-phenotype associations identified by genome-wide association studies (GWAS) have been defined mechanistically, precluding thorough assessment of their impact on human health. We conducted an expression quantitative trait loci (eQTL) mapping analysis in human erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (RBC). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine-mapped the genetic signal to an erythroid-specific enhancer bound by GATA1 and TAL1. These results illustrate the importance to combine transcriptome, epigenome, and genome editing approaches in phenotype-relevant cells to characterize non-coding regulatory elements associated with human complex diseases and traits. Our studies suggest ATP2B4 as a potential target to modulate RBC hydration in erythroid disorders and malaria infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98992 | GEO | 2017/07/17

SECONDARY ACCESSION(S): PRJNA387083

REPOSITORIES: GEO

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An erythroid-specific enhancer of ATP2B4 mediates red blood cell hydration and malaria susceptibility [RNA-seq]

Project description:Few genotype-phenotype associations identified by genome-wide association studies (GWAS) have been defined mechanistically, precluding thorough assessment of their impact on human health. We conducted an expression quantitative trait loci (eQTL) mapping analysis in human erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (RBC). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine-mapped the genetic signal to an erythroid-specific enhancer bound by GATA1 and TAL1. These results illustrate the importance to combine transcriptome, epigenome, and genome editing approaches in phenotype-relevant cells to characterize non-coding regulatory elements associated with human complex diseases and traits. Our studies suggest ATP2B4 as a potential target to modulate RBC hydration in erythroid disorders and malaria infection.

2017-06-23 | GSE90878 | GEO

An erythroid-specific enhancer of ATP2B4 mediates red blood cell hydration and malaria susceptibility

Project description:An erythroid-specific enhancer of ATP2B4 mediates red blood cell hydration and malaria susceptibility

| PRJNA386912 | ENA

FAIRE-chip in CHRF-288-11 and K562 cells

Project description:Maps of open chromatin in a megakaryocytic (CHRF-288-11) and an erythroblastoid (K562) cell line using the formaldehyde-assisted isolation of regulatory elements (FAIRE) method. We profiled chromatin structure at 62 non-redundant genetic loci representing all known associations (as of November 2009, CEU population) with 11 cardiovascular traits: coronary artery disease (CAD), (early-onset) myocardial infarction (MI), mean platelet volume (MPV), platelet counts (PLT), platelet signaling (PLS), white blood cell counts (WBC), red blood cell counts (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), systolic blood pressure (SBP), diastolic blood pressure (DBP), hypertension (HYP). A total of 4 experiments: FAIRE using two different cross-linking times (8 and 12 min) in two cell types (CHRF-288-11 and K562 cells).

2011-07-01 | E-GEOD-25716 | biostudies-arrayexpress

FAIRE-chip in CHRF-288-11 and K562 cells

2011-07-01 | GSE25716 | GEO

Dynamic transcriptional response of Microcoleus vaginatus to hydration and dehydration in a desert biological soil crust

Project description:Biological soil crusts (BSCs) are cyanobacteria-dominated microbial communities that cover extensive portions of the world’s arid and semi-arid deserts. The infrequent periods of hydration are often too short to allow for dormancy strategies based on sporulation; consequently, survival is based on the unique capabilities of vegetative cells to resuscitate from and re-enter a stress resistant dormant state, one of which is migration within the crust layers in response to hydration. In this study, we sought to characterize the events that govern the emergence of the dominant cyanobacterium from dormancy, its subsequent growth, and the events triggered by re-desiccation and a transition back to dormant state. We performed a 48 hour laboratory wetting experiment of a desert BSC and tracked the response of Microcoleus vaginatus using a whole genome transcriptional time-course including night/day periods. This allowed the identification of genes with a diel expression pattern, genes involved uniquely in the signaling after hydration and those that contribute primarily to desiccation preparation.

2012-10-30 | GSE40188 | GEO

Expression of proinflammatory genes in epidermal keratinocytes is regulated by the hydration status.

Project description:We hypothesized that treatment of the injured skin with occlusion limits TEWL and results in a phenotype of epithelial response that more closely resembles mucosa. Here we addressed whether different hydration conditions change gene expression patterns in epidermis using microarray study in rabbit partial-thickness incisional wound. Microarray on epidermis showed that global expression patterns of the genes in full occluded vs. non-occluded wounds are distinct. Many genes - including IL-1β, IL-8, TNF-α, and COX-2-upregulated in skin environment were also upregulated in non-occluded wounds. Simulating increased TEWL showed increased expression of proinflammatory genes in human ex vivo skin culture (HESC) and stratified keratinocytes. Microarray on epidermis showed that global expression patterns of the genes in full occluded vs. non-occluded wounds are distinct.

2012-12-01 | GSE42653 | GEO

Dynamic transcriptional response of Microcoleus vaginatus to hydration and dehydration in a desert biological soil crust

2012-10-30 | E-GEOD-40188 | biostudies-arrayexpress

Transcriptomic analysis of Responsive and Non-responsive Human NK cells to Plasmodium falciparum-infected red blood cells

Project description:NK cells are important cells of the innate immune system that respond to malaria infection in human. Howver, NK cell responses to malaria infection vary significantly in the human population. Base on their ability to kill infected red blood cells (iRBC), NK cells from malaria-naive individuals can be classified as responsive or non-responsive. NK cells used for microarray was obtained as follows: 10^6 NK cells were cocultured with either 10^5 iRBC at a starting parasitemia of 0.5% or with the same amount of RBC for 96 hours. Thereafter live NK cells were purified by FACS and RNA extracted via Trizol method. RNA quality was assessed by electrophoretic assay on the Agilent 2100 Bioanalyzer using a Nano chip (Agilent RNA 6000 Nano chip). RNA with a RIN value of >7.0 was used for genome-wide transcriptional analysis by microarray using HumanHT-12 v4 BeadChip (Illumina).

2018-08-30 | E-MTAB-6574 | biostudies-arrayexpress

Homo sapiens

Project description:An erythroid-specific enhancer of ATP2B4 mediates red blood cell hydration and malaria susceptibility [genotype]

| PRJNA387083 | ENA

Isosorbide di-(linoleate/oleate) stimulates pro-differentiation gene expression to restore the epidermal barrier and improve skin hydration

Project description:The breakdown of epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we generated a novel compound, isosorbide di-(linoleate/oleate) (IDL), by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared to those of ethyl linoleate/oleate (EL), which has previously been shown to improve skin barrier function. Both IDL and EL down-regulated inflammatory gene expression, but IDL more effectively up-regulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased abundance of epidermal barrier proteins (filaggrin and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also down-regulated expression of “unhealthy skin signature” genes linked to loss of epidermal homeostasis and uniquely repressed an interferon-inducible co-expression module activated in multiple skin diseases including psoriasis. In a double-blind placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for treatment of xerotic pruritic skin.

2020-11-16 | GSE157932 | GEO

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