Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei

Abstract

Summary Using published high-resolution data on S-phase replication timing, we determined the three-dimensional (3D) nuclear arrangement of 33 very-early-replicating and 31 very-late-replicating loci. We analyzed diploid human, non-human primate and rearranged tumor cells by 3D fluorescence in situ hybridization with the aim of investigating the impact of chromosomal structural changes on the nuclear organization of these loci. Overall, their topology was found to be largely conserved between cell types, species and in tumor cells. Early-replicating loci were localized in the nuclear interior, whereas late-replicating loci showed a broader distribution with a higher preference for the periphery than for late-BrdU-incorporation foci. However, differences in the spatial arrangement of early and late loci of chromosome 2, as compared with those from chromosome 5, 7 and 17, argue against replication timing as a major driving force for the 3D radial genome organization in human lymphoblastoid cell nuclei. Instead, genomic properties, and local gene density in particular, were identified as the decisive parameters. Further detailed comparisons of chromosome 7 loci in primate and tumor cells suggest that the inversions analyzed influence nuclear topology to a greater extent than the translocations, thus pointing to geometrical constraints in the 3D conformation of a chromosome territory.

Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles

“…[33][34][35] The strongest functional evidence linking chromosome architecture and cellular function was recently demonstrated in rod cell nuclei. 36 The authors convincingly demonstrated regular and inverted chromosomal architecture in rod cells, and this architecture was associated with diurnal and nocturnal vision.…”

Does positioning of chromosomes 8 and 21 in interphase drive t(8;21) in acute myelogenous leukemia?

“…Furthermore, non-random positioning in interphase nuclei is known to be of importance for genomic stability and formation of chromosome aberrations. Tissue specificity of chromosomal translocations could be due to tissue specific genome organization [5][6], and a positive correlation between spatial proximity of chromosomes/ genes in interphase nuclei and translocation frequencies was shown [5][6][7][8][9][10]. Three-dimensional (3D) fluorescence in situ hybridization (FISH) analysis became a major tool 3D-positioning of chromosomes 8 and 21 in AML for studying this higher order chromatin organization in the cell nucleus [4; 11-15].…”

The Structure and Function of Chromatin and Chromosomes

“…Many lines of evidence suggest the functional significance of genome architecture, including the existence of chromosomes territories [1], the correlation between radial positioning of chromosomes with gene density, transcriptional activity, replication timing and chromosome size [2][3][4][5], the tissue-specific spatial configurations of chromosomes relative to one another [6,7], the co-localization of disparate DNA elements into functionally defined aggregates or "factories" [9][10][11][12][13], and the predisposition to human disease, including cancer by predisposition to acquisition of karyotypic defects [14][15][16][17]. Collectively, these various lines of evidence indicate an intimate relationship between genome structure and function.…”