A CRISPR view of the genome in living cells: cell cycle and genomic distance dependent dynamics of chromosomal loci

Abstract

In contrast to the well-studied condensation and folding of chromosomes during mitosis, their dynamics during interphase are less understood. We deployed our newly developed, brightness-enhanced CRISPR-based DNA imaging system (CRISPR-Sirius, Ma et al., 2018) to track the dynamics of genomic loci situated kilobases to megabases apart on a single chromosome. Two distinct modes of dynamics were resolved: local movements as well as translational movements of the entire domain within the nucleoplasm. The magnitude of both of these modes of movements increased from early to late G1, whereas the translational movements were reduced in early S. The local fluctuations decreased slightly in early S and more markedly in mid-late S. These results (Ma el al. J. Cell Biol., in press) suggest an ongoing compaction-relaxation dynamic of the interphase chromosome fiber, operating concurrently with changes in the extent of overall translational movements of loci in the 4D nucleome. The former possibility was anticipated some time ago (Pederson, 1972) and the latter shortly thereafter (Crick, 1978). It is too soon to know the full meaning of these interphase chromosome dynamics but all the tools to access this dimension of genome biology are fortunately now at hand. References: Crick, F.H.C. 1978. Chromosome structure and function. Future prospects. Eur. J. Biochem. 83: 1-3. Ma, H., Tu, L.-C., Naseri, A., Chung, Y.C., Grunwald, D., Zhang, S. and Pederson, T. 2018. Engineered CRISPR RNA scaffolds with enhanced stability for signal amplification in genome imaging. Nature Methods 15: 928-931. Mazia, D. 1987. The chromosome cycle and the centrosome cycle in the mitotic cycle. Intl. Rev. Cytol. 100: 49-92. Pederson, T. 1972. Chromatin structure and the cell cycle. Proc. Natl. Acad. Sci. USA 69: 2224-2228. Funding: Supported by NIH grants K99 GM126810 (L.-C.T), R01 GM102515 (S.Z.), U01 EB021238 (D.G.) and U01 DA040588 (T.P.). The latter two grants are part of the 4D Nucleome Initiative of the NIH Common Fund.