Abstract
In the last decade, the developments of novel technologies, such as Hi-C or GAM methods, allowed to discover that chromosomes in the nucleus of mammalian cells have a complex spatial organization, encompassing the functional contacts between genes and regulators. In this work, we review recent progresses in chromosome modeling based on polymer physics to understand chromatin structure and folding mechanisms. As an example, we derive in mouse embryonic stem cells the full 3D structure of the Bmp7 locus, a genomic region that plays a key role in osteoblastic differentiation. Next, as an application to Neuroscience, we present the first 3D model for the mouse orthologoue of the Williams–Beuren syndrome 7q11.23 human locus. Deletions and duplications of the 7q11.23 region generate neurodevelopmental disorders with multi-system involvement and variable expressivity, and with autism. Understanding the impact of such mutations on the rewiring of the interactions of genes and regulators could be a new key to make sense of their related diseases, with potential applications in biomedicine.
Highlights
Novel and different technologies, such as Hi-C (Lieberman-Aiden et al, 2009) and GAM (Beagrie et al, 2017), are revealing that, in higher organisms, chromatin is folded in the nucleus of cells with complex 3D spatial organization (Lanctôt et al, 2007; Misteli, 2007; Bickmore and van Steensel, 2013; Tanay and Cavalli, 2013; Dekker and Mirny, 2016)
As an application of potential interest to neurogenetics, we reconstruct for the first time the three dimensional structure of the 7q11.23 locus, where structural variants are associated with severe disorders such as autism and Williams-Beuren syndrome (e.g., Sanders et al, 2011 and ref.s therein)
We reviewed recent developments in polymer physics models to understand the 3D structure of genomic loci and the connection to human diseases
Summary
Novel and different technologies, such as Hi-C (Lieberman-Aiden et al, 2009) and GAM (Beagrie et al, 2017), are revealing that, in higher organisms, chromatin is folded in the nucleus of cells with complex 3D spatial organization (Lanctôt et al, 2007; Misteli, 2007; Bickmore and van Steensel, 2013; Tanay and Cavalli, 2013; Dekker and Mirny, 2016). To test this pure state mixture model of chromatin we compare the experimental average pairwise contact probability P(s) of two generic loci separated by a genomic distance s with the theoretical P(s). Few of the binding domains (e.g., type 5 and 11, Figures 5C,D) do not correlate with the considered epigenomic features, and result to be associated with the central, gene poor, region of the locus.In summary, our polymer model of the murine genomic region syntenic with the 7q11.23 locus in human provides a first reconstruction of the ensemble of 3D conformation of the locus. A complex network of higher-order interactions of the locus emerges from our analysis, whose rewiring could be important to understand the effects of disease associated structural variants
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