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

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

PROVIDER: PRJNA386912 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5077160_1.fastq.gz	Fastqsanger.gz
	SRR5077160_2.fastq.gz	Fastqsanger.gz
	SRR5077170_1.fastq.gz	Fastqsanger.gz
	SRR5077170_2.fastq.gz	Fastqsanger.gz
	SRR5077161_1.fastq.gz	Fastqsanger.gz

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

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.

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

Project description:The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in 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 of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection.

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

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Immunogenomic profile at baseline predicts host susceptibility to clinical malaria

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

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

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