Numerous studies indicate that the genome of higher eukaryotes is organized into distinct chromosome territories and that the 3-D arrangement of these territories may be closely connected to genomic function and the global regulation of gene expression. Despite this progress, the degree of non-random arrangement remains unclear and no overall model has been proposed for chromosome territory associations. To address this issue, a re-FISH approach was combined with computational analysis to analysis the pair-wise associations for six pairs of human chromosomes (chr #1, 4, 11, 12, 16, 18) in the G(0) state of normal human WI38 lung fibroblast and MCF10A epithelial breast cells. Similar levels of associations were found in WI38 and MCF10A for several of the chromosomes whereas others showed striking differences. A novel computational geometric approach, the generalized median graph (GMG), revealed a preferred probabilistic arrangement distinct for each cell line. Statistical analysis demonstrated that approximately 50% of the associations depicted in the GMG models are present in each individual nucleus. A nearly twofold increase of chromosome 4/16 associations in a malignant breast cancer cell line (MCFCA1a) compared to the related normal epithelial cell line (MCF10A) further demonstrates cancer related changes in chromosome arrangements. Our findings of highly preferred chromosome association profiles that are cell type specific and undergo alterations in cancer cells, lead us to propose a probabilistic chromosome code whereby the 3-D association profile of chromosomes contributes to the functional landscape of the cell nucleus, the global regulation of gene expression and the epigenetic state of chromatin.
Lichen scrofulosorum is an uncommon but not rare cutaneous manifestation of tuberculosis. A high index of suspicion and awareness is required for diagnosis. Systemic tuberculosis is often associated with LS and a prior BCG inoculation does not protect against development of LS. Response to antitubercular treatment is good irrespective of the presence or absence of associated tubercular focus.
There is growing evidence that chromosome territories have a probabilistic non-random arrangement within the cell nucleus of mammalian cells. Other than their radial positioning, however, our knowledge of the degree and specificity of chromosome territory associations is predominantly limited to studies of pair-wise associations. In this study we have investigated the association profiles of eight human chromosome pairs (numbers 1, 2, 3, 4, 6, 7, 8, 9) in the cell nuclei of G(0)-arrested WI38 diploid lung fibroblasts. Associations between heterologous chromosome combinations ranged from 52% to 78% while the homologous chromosome pairs had much lower levels of association (3-25%). A geometric computational method termed the Generalized Median Graph enabled identification of the most probable arrangement of these eight chromosome pairs. Approximately 41% of the predicted associations are present in any given nucleus. The association levels of several chromosome pairs were very similar in a series of lung fibroblast cell lines but strikingly different in skin and colon derived fibroblast cells. We conclude that a large subset of human chromosomes has a preferred probabilistic arrangement in WI38 cells and that the resulting chromosomal associations show tissue origin specificity.
Higher order chromatin organization in concert with epigenetic regulation is a key process that determines gene expression at the global level. The organization of dynamic chromatin domains and their associated protein factors is intertwined with nuclear function to create higher levels of functional zones within the cell nucleus. As a step towards elucidating the organization and dynamics of these functional zones, we have investigated the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1g, nascent transcript sites (TS), active DNA replicating sites in early S-phase (PCNA) and RNA polymerase II sites. We report close associations among these different sites with proximity values specific for each combination. Analysis of matrin 3 and SAF-A sites demonstrates that these nuclear matrix proteins are highly proximal with the functionally related sites as well as to each other and display closely aligned and overlapping regions following application of the minimal spanning tree (MST) algorithm to visualize higher order network-like patterns. Our findings suggest that multiple factors within the nuclear microenvironment collectively form higher order combinatorial arrays of function. We propose a model for the organization of these functional neighborhoods which takes into account the proximity values of the individual sites and their spatial organization within the nuclear architecture. J. Cell. Biochem. 105: 391-403, 2008. ß 2008 KEY WORDS: RNA POLYMERASE II SITES; HP1g SITES; REPLICATION SITES; TRANSCRIPTION SITES; CELL NUCLEUS; PROLIFERATING CELL NUCLEAR ANTIGEN; NUCLEAR MATRIX; MATRIN 3; SAF-A; COMPUTER IMAGE SEGMENTATION; PROXIMITY ANALYSIS; PATTERN RECOGNITION IMAGE ANALYSIS; MINIMAL SPANNING TREE NETWORKS D espite significant advances in molecular biology and biochemistry, our understanding of the nucleus is at its infancy. The genome is more than a linear sequence of DNA [Misteli, 2007] and is segmented into chromosomes which occupy distinct territories in the interphase cell nucleus [Cremer et al., 2001]. Chromatin within these chromosomes is arranged into multiple levels of hierarchical organization from the nucleosomal 10 nm arrays to the 30 nm fibers to chromatin loops and higher order domains [Berezney, 2002;Cremer et al., 2006;Razin et al., 2007]. Although the eukaryotic nucleus is devoid of any internal membranes, it introduces an incredible level of complexity and several layers of control, which regulate the genomic functions and increase the efficiency of processivity and enzyme regulatory mechanisms. Moreover, the compartmentalization of genomic functions and factors that mediate these functions suggests a high level of structural organization [Berezney et al., 1996;Strouboulis Journal of Cellular Biochemistry ARTICLE Journal of Cellular Biochemistry 105: 391-403 (2008) 391Abbreviations used: DAPI, 4 0 ,6-diamidino-2-phenylindole; HP1g, heterochromatin protein 1, gamma; MST, minimal span...
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