High order chromatin architecture shapes the landscape of chromosomal alterations in cancer

Harvard University, Program in Biophysics, Boston, Massachusetts, USA.
Nature Biotechnology (Impact Factor: 41.51). 11/2011; 29(12):1109-13. DOI: 10.1038/nbt.2049
Source: PubMed


The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy-number alterations (SCNAs) in cancer. Using a maximum likelihood approach, we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule model. This analysis suggests that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and that purifying selection, as well as positive selection, influences SCNAs during somatic evolution of cancer cells.

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    • "In both scenarios, genome reorganization precedes gene expression changes, suggesting a potential causal relationship (Apostolou et al., 2013; Phillips- Cremins et al., 2013; Wei et al., 2013; Zhang et al., 2013). Higher-order genome organization has been shown to significantly influence the distribution of genomic aberrations in both immortalized somatic cells and cancer cells, but the underlying mechanism remains elusive (De and Michor, 2011; Fudenberg et al., 2011; Koren et al., 2012; Schuster-Bö ckler and Lehner, 2012). One method of mapping genomic organization is by segmenting the genome into domains based on replication timing, which occurs in a tightly regulated cell-type-specific manner (Gilbert et al., 2010). "
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    ABSTRACT: Cell-fate change involves significant genome reorganization, including changes in replication timing, but how these changes are related to genetic variation has not been examined. To study how a change in replication timing that occurs during reprogramming impacts the copy-number variation (CNV) landscape, we generated genome-wide replication-timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early- and late-replicating domains in iPSCs are differentially affected by copy-number gains and losses and that in particular, CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming.
    Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.03.007 · 8.36 Impact Factor
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    • "During carcinogenesis, the 3D spatial arrangement of chromatin patterns experience translocation and alterations in the spatial density of chromatin at different loci of the nucleus. For example, the large-scale changes in 3D genomic architecture or the changes in spatial distribution of chromosome have been reported in cancer [6,7]. Therefore, we hypothesize that the complex genomic and epigenomic changes in carcinogenesis result in nanoscale structural alterations arising from the changes in the 3D spatial arrangement and the chromatin density variation in the cell nucleus. "
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    ABSTRACT: The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 - 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis. Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations - spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This paper presents a review of current work and discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis. The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.
    BMC Biophysics 02/2014; 7(1):1. DOI:10.1186/2046-1682-7-1 · 2.89 Impact Factor
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    • "We also argue that using a confidence estimation method that accounts for the random polymer looping effect is crucial in order to characterize association of chromatin contacts with other genomic features that relate pairs of loci, such as the two ends of a somatic copy number alteration (SCNA). Two independent studies have shown enrichment of chromatin contacts between SCNA ends (De and Michor 2011; Fudenberg et al. 2011). These studies explicitly control for SCNA length and other potential biases. "
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    ABSTRACT: Our current understanding of how DNA is packed in the nucleus is most accurate at the fine scale of individual nucleosomes and at the large scale of chromosome territories. However, accurate modeling of DNA architecture at the intermediate scale of ~50 kb-10 Mb is crucial for identifying functional interactions among regulatory elements and their target promoters. We describe a method, Fit-Hi-C, that assigns statistical confidence estimates to mid-range intra-chromosomal contacts by jointly modeling the random polymer looping effect and previously observed technical biases in Hi-C data sets. We demonstrate that our proposed approach computes accurate empirical null models of contact probability without any distribution assumption, corrects for binning artifacts and provides improved statistical power relative to a previously described method. High-confidence contacts identified by Fit-Hi-C preferentially link expressed gene promoters to active enhancers identified by chromatin signatures in human embryonic stem cells (ESCs), capture 77% of RNA polymerase II mediated enhancer-promoter interactions identified using ChIA-PET in mouse ESCs, and confirm previously validated, cell line-specific interactions in mouse cortex cells. Incorporating two sets of independent semi-automated genomic annotations in human ESCs, we observe that insulators and heterochromatin regions are hubs for high-confidence contacts while transcription start sites, promoters and strong enhancers are involved in fewer but potentially more targeted contacts. We also observe that regions containing binding peaks of master pluripotency factors such as NANOG and POU5F1 are highly enriched in high-confidence contacts for human ESCs. Furthermore, we show that pairs of loci linked by high-confidence contacts exhibit similar replication timing in human and mouse ESCs and preferentially lie within the boundaries of previously described topological domains for all human and mouse cell lines analyzed here.
    Genome Research 02/2014; 24(6). DOI:10.1101/gr.160374.113 · 14.63 Impact Factor
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