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Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated <i>PLOD2</i> gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Krüppel associated box (KRAB) repressor directed to the <i>PLOD2</i> promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%–70% reduction in <i>PLOD2</i> expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to <i>PLOD2</i> resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete <i>PLOD2</i> silencing. Interestingly, both long-term TGFβ1-induced, as well as unstimulated <i>PLOD2</i> expression, was completely repressed by KRAB, while M.SssI only prevented the TGFβ1-induced <i>PLOD2</i> expression. Targeting transiently expressed dCas9-KRAB resulted in sustained <i>PLOD2</i> repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGFβ1-induced and uninduced <i>PLOD2</i> expression.