CRISPR screening has identified genes and regulatory genomic regions associated with red blood cell (RBC) density, providing new insights into the molecular mechanisms underlying inherited RBC traits.
Genome-wide association studies (GWAS) have identified more than 1,000 genetic loci associated with RBC traits, but the biological functions underlying many of these associations remain poorly understood. To address this gap, researchers conducted pooled CRISPR screens in an erythroid cell line to identify genes and non-coding genomic sequences involved in regulating RBC density.
The investigation targeted 556 candidate genes and genomic sequences located near 2,114 GWAS variants. Following validation, the researchers identified 17 genes and 13 genomic regions associated with RBC density, connecting genetic associations with potential functional mechanisms.
The findings included established RBC regulators, such as ATP2B4, CCND3, and EPOR, alongside less characterised genes, including CHTF8, CTU2, DNASE2, and RAB10. These results expanded the range of candidate genes implicated in the regulation of RBC traits.
The researchers also investigated the role of OXSR1, which encodes a kinase involved in the cellular response to osmotic stress. Deletions in OXSR1 were confirmed to increase cell density, providing experimental evidence of its involvement in this cellular characteristic.
To explore how non-coding genetic variation may influence gene expression, the team combined CRISPR perturbations with RNA sequencing. This approach revealed that a non-coding genomic sequence near the genetic variant rs13255015 regulated the expression of ZFAT in cis and SLC4A1 in trans.
These findings demonstrated how regulatory DNA sequences may influence the activity of multiple genes, offering a potential explanation for the functional effects of genetic variants identified through GWAS. The results also highlighted the value of combining genome editing with gene expression analysis to investigate the mechanisms connecting genetic variation with cellular traits.
The study provides experimental evidence to support the functional characterisation of genetic associations with RBC density. By identifying both known and previously less characterised candidate genes, the research offers new directions for investigating the molecular regulation of RBC traits.
Reference
Brosseau N et al. Pooled CRISPR screens identify genes and non-coding genomic regions that regulate red blood cell density. Commun Biol. 2026;DOI: https://doi.org/10.1038/s42003-026-11204-w.
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