The spatiotemporal regulation of three-dimensional (3D) genome dynamics has been implicated in various genome functions including gene transcription, DNA recombination, DNA replication, and DNA repair (Bickmore, 2013). However, mechanistic studies to dissect the factors regulating genome dynamics and the causal roles of 3D genome structure in physiological processes have been significantly limited by experimental tools. Recently developed CRISPR/dCas9 genome labeling strategies allow the tracking of the particular genome regions in live cells (Chen et al., 2013). Various approaches have been developed to amplify the labeling signals and to reduce the non-specific backgrounds (Wu et al., 2019). In addition, dCas9 knock-in mouse strains were developed for tracking genome dynamics in live animals (Wang et al., 2016). However, most of the current dCas9 imaging studies are limited to reveal or confirm the correlations between dynamics of particular genome regions and its potential physiological functions, while more mechanistic studies are still required. To directly test the causal roles of 3D genome positioning in regulating genome functions, a CRISPR-GO system was developed recently to alter the nuclear localization of dCas9-targeted genome loci (Wang et al., 2018). On the other hand, the CRISPRii strategy was used to study the effect of silencing shelterin subunit on telomere dynamics in vivo (Duan et al., 2018). Previous studies demonstrated that in combination with truncated gRNAs, the catalytically active Cas9 could also behave like dCas9 and lead to targeted activation and repression (Dahlman et al., 2015; Kiani et al., 2015). We propose that such combination could also be used for genome labeling and extended for mechanistic study of factors regulating genome dynamics.