Construct for epigenetic modification and its use in the silencing of genes

A single molecule for stably silencing expression of a target gene of interest that is endogenous to a human primary cell via targeted epigenomic modification, said molecule comprising a fusion protein or a nucleic acid encoding said fusion protein, wherein said fusion protein comprises the following components:

• a) a Krüppel-associated box (KRAB) effector domain,
• b) a DNA binding domain capable of binding to said target gene,
• c) a human DNA methyltransferase DNMT3A or a homolog thereof that exhibits at least 90% sequence identity to SEQ ID NO:
• 3, and
• d) a murine DNA methyltransferase Dnmt3L or a homolog thereof that exhibits at least 90% sequence identity to SEQ ID NO:
• 5,
• whereby components a), b), c) and d) are linked to each other either directly or via at least one linker.