Multiple sclerosis is the most common chronic inflammatory and neurodegenerative disease of the central nervous system, highly influenced by genetic factors in combination with the epigenetic and environmental factors. Among the strongest genetic risk factors is the DR15 haplotype, particularly the class II HLA-DRB1*15:01 allele, whose expression is highly regulated by the Class II translational activator, CIITA. This study aimed to investigate how targeted DNA methylation influences the expression of HLA class II genes, specifically focused on CIITA. THP-1 cells stably expressing dCas9-DNMT3a were treated with different pro-inflammatory stimuli, such as hIFN-γ and LPS, to determine under which conditions there is an increased expression of HLA class II genes in these cells. This resulted in the establishment of a baseline immune activation model, which was later used to assess how targeted DNA methylation at the CIITA promoter and HLA-DRB1*15:01 locus influences gene expression. Guide RNAs targeting promoter regions of CIITA, namely pIII and pIV, were delivered via lentiviral transduction, and the changes in gene expression and promoter methylation were assessed using RT-qPCR and pyrosequencing. The stimulation of THP-1 stable cells with hIFN-γ showed robustly induced expression of CIITA and HLA class II genes, while LPS alone showed no effect. The results of gRNA-mediated targeting showed minor changes in expression levels, and the pyrosequencing results revealed no consistent increase in DNA methylation at the targeted promoter regions. These findings highlight both the potential but also the current limitations of dCas9-DNMT3a-mediated epigenetic editing, with future improvements in gRNA design, delivery efficiency, and further research in target selection needed for more accurate results and better effect in transcriptional silencing. This study provides insights into epigenetic regulation of immune genes relevant to multiple sclerosis, but further investigation is needed.