Prokaryotic type II CRISPR-Cas systems can be adapted to enable targeted genome 
modifications across a range of eukaryotes. Here we engineer this system to 
enable RNA-guided genome regulation in human cells by tethering transcriptional 
activation domains either directly to a nuclease-null Cas9 protein or to an 
aptamer-modified single guide RNA (sgRNA). Using this functionality we developed 
a transcriptional activation-based assay to determine the landscape of 
off-target binding of sgRNA:Cas9 complexes and compared it with the off-target 
activity of transcription activator-like (TALs) effectors. Our results reveal 
that specificity profiles are sgRNA dependent, and that sgRNA:Cas9 complexes and 
18-mer TAL effectors can potentially tolerate 1-3 and 1-2 target mismatches, 
respectively. By engineering a requirement for cooperativity through offset 
nicking for genome editing or through multiple synergistic sgRNAs for robust 
transcriptional activation, we suggest methods to mitigate off-target phenomena. 
Our results expand the versatility of the sgRNA:Cas9 tool and highlight the 
critical need to engineer improved specificity.