Permanent epigenetic gene silencing

A composition for silencing a target gene, genetic element or splice variant, wherein the composition comprises a combination of artificial transcription repressors (ATRs) selected from the group consisting of: (a) and (b); (a) and (c); (b) and (c); (b) and (d); and (c) and (d); or polynucleotides encoding them, wherein: (a) is an ATR comprising a DNA-binding domain operably linked to a KRAB domain; (b) is an ATR comprising a DNA-binding domain operably linked to a DNMT3A, DNMT3B, or DNMT1 domain; (c) is an ATR comprising a DNA-binding domain operably linked to a DNMT3L domain; and (d) is an ATR comprising a DNA-binding domain operatively linked to a SETDB1 domain, and wherein the DNA-binding domains of the different ATRs: (i) bind to binding sites independently selected from the group consisting at: a binding site within the target gene or genetic element; a binding site within a regulatory sequence for the target gene; and a binding site within a splice site for the target gene; and (ii) bind to different binding sites or to the same binding site.