β-hemoglobinopathies are severe genetic disorders caused by mutations affecting the production of the β-globin chain. The clinical-severity of these pathologies can be effectively mitigated by the reactivation of γ-globin (HBG) genes, resulting in elevated production of fetal hemoglobin. In this study, we aimed to investigate the epigenetic landscape of the γ-globin promoter in HUDEP-2 cells and utilize designer epigenetic modifiers (DEMs) to activate the HBG gene through precise epigenome editing.. We confirmed the presence of epigenetic marks indicative of gene inactivation at the HBG promoters, such as enriched H3K9me3 and H3K27me3 and high DNA methylation, via ChIP-qPCR and bisulfite sequencing, respectively. We then developed activating DEMs targeting three different positions within the proximal γ-globin promoter and tested their ability to reactivate HBG expression in HEK293T cells that typically do not express γ-globin. We delivered DEM to the cells in form of in vitro transcribed mRNA via lipofection. Two days later, we evaluated HBG expression levels using quantitative polymerase chain reaction (qPCR). We show that the three DEMs were highly efficient in reactivating HBG expression with the most effective exhibiting a remarkable 3 to 25-fold increase in γ-globin levels depending upon the targeted region. Current efforts aims at identifying more potent combinations of effectors and novel target sites to maximize long-term expression of the γ-globin gene, followed by validation in clinically relevant hematopoietic stem cells (HSCs). This approach holds great potential as a novel strategy for the treatment of β-Hemoglobinopathies and paves the way for a new era of therapeutics.