biorxiv

DNA methylation is traditionally associated with gene silencing, but its causal relationship and role in shaping cell fate decisions still need to be fully elucidated. Here, we conducted a genome-wide analysis to investigate the relationship between DNA methylation and gene expression at gene regulatory regions in human immune cells. By utilizing CRISPR-dCas9 DNA methylation editing tools, we successfully established a cause-and-effect relationship between the methylation levels of the promoter of the Interleukin1-receptor antagonist (IL1RN) gene and its expression. Notably, we observed that modifying the DNA methylation status of the IL1RN promoter is sufficient to alter the acquisition of the human myeloid cell fate and change the cellular response to inflammatory stimuli, resulting in abnormal cytokine release and distinctive capacity to support cancer growth.