Epigenetic-dependent regulatory mechanism of rs12041331 in PEAR1 expression. The major G allele of the CpG-SNP introduces a CpG site in the enhancer region that binds with higher affinity to several nuclear proteins than the A allele. At the same time, the G-methylated allele marks higher methylation at CGI1, the CpG island located at the untranslated region of PEAR1 that contains several binding sites for CTCF, important for chromosome looping and architecture. When higher methylation is present, CTCF binds with lower affinity to the CGI1 region, liberating the enhancer activity of intron 1, where the CpG-SNP is also located. On the contrary, lower methylation at CGI1 is associated with the minor A allele of the CpG-SNP, reinforcing CTCF binding and partially inhibiting gene expression. This model advances a positive effect of methylation on gene expression and is in accordance with the association between increasing methylation and PEAR1 expression during early MK progenitor development.