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(57 ) ABSTRACT 8 ,871 ,445 B2 10 / 2014 Le Cong et al . 8 , 889 , 356 B2 11/ 2014 Zhang The present disclosure provides systems, compositions and 8 , 895 ,308 B1 11/ 2014 Zhang et al. 8 , 906 , 616 B2 12 / 2014 Zhang et al. methods for regulating expression of a target polynucleotide 8 , 932 , 814 B2 1 /2015 Le Cong et al. in a cell. The systems, compositions and methods comprise 8 , 945, 839 B2 2 / 2015 Zhang a chimeric receptor polypeptide comprising a G -protein 8 , 993 , 233 B2 3 / 2015 Zhang et al. 8 , 999 , 641 B2 4 / 2015 Zhang et al. coupled receptor (GPCR ) or a fragment thereof, a chimeric 9 , 023 , 649 B2 5 / 2015 Mali et al . adaptor polypeptide, at least one actuator moiety and a 9 , 234 , 213 B2 1 / 2016 Wu cleavage moiety . 9 , 260 , 752 B1 2 / 2016 May et al. 9 , 580, 480 B2 2 / 2017 Lu et al. 9 , 587, 020 B2 3 /2017 Wu et al . 30 Claims, 49 Drawing Sheets US 9 ,856 ,497 B2 Page 2 References Cited WO 2015139139 9 / 2015 ( 56 ) WO 2015142661 9 /2015 U . S . 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