Genetic variants within silencer elements shape human blood cell phenotype diversity

In K562 cells, ReSE screening of 14,720 non-coding variants identified 805 sequences with differential silencer activity, including 425 loss-of-silencer-function and 380 gain-of-silencer-function candidates.

• Why it matters: Non-coding variants are linked to blood cell trait variation, but how variants within silencer elements affect gene regulation is not well defined, limiting mechanistic interpretation of fine-mapped loci.
• What they did: Using ReSE, the study screened sequences encompassing 14,720 variants from fine-mapped loci for 15 blood cell traits, then validated allele-dependent repression with luciferase reporters and endogenous editing.
• The result: Editing selected variants altered nearby gene expression, and K562 cells with the rs2857078 alternative allele showed downregulated globin expression and reduced mature erythrocyte markers after erythroid differentiation, while integrated chromatin accessibility and conservation prioritized functional silencer variants despite low fine-mapping posterior inclusion probabilities.