Chromatin conformation signatures of cellular differentiation

Department of Biochemistry and McGill Cancer Center, McGill University, 3655 Promenade Sir-William-Osler, Montréal, H3G1Y6, Canada.
Genome biology (Impact Factor: 10.81). 05/2009; 10(4):R37. DOI: 10.1186/gb-2009-10-4-r37
Source: PubMed


One of the major genomics challenges is to better understand how correct gene expression is orchestrated. Recent studies have shown how spatial chromatin organization is critical in the regulation of gene expression. Here, we developed a suite of computer programs to identify chromatin conformation signatures with 5C technology We identified dynamic HoxA cluster chromatin conformation signatures associated with cellular differentiation. Genome-wide chromatin conformation signature identification might uniquely identify disease-associated states and represent an entirely novel class of human disease biomarkers.

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Available from: Mathieu Rousseau, Jul 11, 2015
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    • "The high 5C interactions across HoxD that we detected in undifferentiated mESCs are strongly reduced in D3 cells but, like H3K27me3, are not completely lost (Fig. 2A,B; Supplemental Fig. S1C). This is consistent with the visible unfolding of HoxD chromatin seen upon mESC differentiation (Fig. 2C,D) and the loss of long-range 3C and 5C contacts reported upon HOXA activation (Fraser et al. 2009; Ferraiuolo et al. 2010). FISH using probe pairs across the whole region interrogated by 5C (Supplemental Table S1) confirmed a visible chromatin decompaction during differentiation and that this is restricted to the region overlapping HoxD and Evx2 (Hoxd13–Hoxd3; Prox–Hoxd10) (Fig. 2D; Supplemental Tables S2, S3). "
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    ABSTRACT: Although important for gene regulation, most studies of genome organization use either fluorescence in situ hybridization (FISH) or chromosome conformation capture (3C) methods. FISH directly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. The frequency at which sequences are ligated together by formaldehyde cross-linking can be measured genome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3C should therefore give the same views of genome organization, but this has not been tested extensively. We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmental and activity states and in the presence or absence of epigenetic regulators. We identified situations in which the two data sets are concordant but found other conditions under which chromatin topographies extrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do not always reflect spatial proximity, with ligation occurring between sequences located hundreds of nanometers apart, influenced by nuclear environment and chromatin composition. We conclude that results obtained at high resolution with either 3C methods or FISH alone must be interpreted with caution and that views about genome organization should be validated by independent methods. © 2014 Williamson et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 28(24):2778-2791. DOI:10.1101/gad.251694.114 · 10.80 Impact Factor
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    • "The number n of windows may vary from one study to another: Lieberman-Aiden et al. (2009) considered an Mb resolution, whereas Dixon et al. (2012) went deeper and used windows of 100 kb. Blocks of higher intensity arise among this matrix, revealing both cis-and trans-interacting regions (Fraser et al., 2009). "
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    ABSTRACT: Motivation: The spatial conformation of the chromosome has a deep influence on gene regulation and expression. Hi-C technology allows the evaluation of the spatial proximity between any pair of loci along the genome. It results in a data matrix where blocks corresponding to (self-)interacting regions appear. The delimitation of such blocks is critical to better understand the spatial organization of the chromatin. From a computational point of view, it results in a 2D segmentation problem. Results: We focus on the detection of cis-interacting regions, which appear to be prominent in observed data. We define a block-wise segmentation model for the detection of such regions. We prove that the maximization of the likelihood with respect to the block boundaries can be rephrased in terms of a 1D segmentation problem, for which the standard dynamic programming applies. The performance of the proposed methods is assessed by a simulation study on both synthetic and resampled data. A comparative study on public data shows good concordance with biologically confirmed regions. Availability and implementation: The HiCseg R package is available from the Comprehensive R Archive Network and from the Web page of the corresponding author. Contact:
    Bioinformatics 09/2014; 30(17):i386-i392. DOI:10.1093/bioinformatics/btu443 · 4.98 Impact Factor
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    • "The chromosome conformation capture (3C) and 3C-carbon copy (5C) techniques were used as previously described to characterize the chromatin organization of a region containing the HOXA gene cluster [38,51]. The experimental design and the procedure used to generate our 3C and 5C datasets are described in detail in Additional file 1: Supplementary Materials and methods. "
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    ABSTRACT: Background Although genetic or epigenetic alterations have been shown to affect the three-dimensional organization of genomes, the utility of chromatin conformation in the classification of human disease has never been addressed. Results Here, we explore whether chromatin conformation can be used to classify human leukemia. We map the conformation of the HOXA gene cluster in a panel of cell lines with 5C chromosome conformation capture technology, and use the data to train and test a support vector machine classifier named 3D-SP. We show that 3D-SP is able to accurately distinguish leukemias expressing MLL-fusion proteins from those expressing only wild-type MLL, and that it can also classify leukemia subtypes according to MLL fusion partner, based solely on 5C data. Conclusions Our study provides the first proof-of-principle demonstration that chromatin conformation contains the information value necessary for classification of leukemia subtypes.
    Genome Biology 04/2014; 15(4):R60. DOI:10.1186/gb-2014-15-4-r60 · 10.81 Impact Factor
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