An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility.
Authors
Lessard, SGatof, E
Beaudoin, M
Schupp, P
Sher, F
Ali, Adnan
Prehar, S
Kurita, R
Nakamura, Y
Baena, Esther
Ledoux, J
Oceandy, D
Bauer, D
Lettre, G
Affiliation
Montreal Heart Institute and Universite de Montreal, Montreal, Quebec, CanadaIssue Date
2017-08-01
Metadata
Show full item recordAbstract
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.Citation
An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility. 2017, 127 (8):3065-3074 J. Clin. Invest.Journal
The Journal of Clinical InvestigationDOI
10.1172/JCI94378PubMed ID
28714864Type
ArticleLanguage
enISSN
1558-8238ae974a485f413a2113503eed53cd6c53
10.1172/JCI94378
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