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The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.

Original publication




Journal article


Nature methods

Publication Date





611 - 616


Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA.


Humans, Recombinant Fusion Proteins, Repressor Proteins, RNA, Guide, Gene Expression Regulation, Gene Silencing, Genes, Synthetic, Methyl-CpG-Binding Protein 2, HEK293 Cells, CRISPR-Cas Systems, CRISPR-Associated Protein 9