Large-Scale Functional Organization of Long-Range Chromatin Interaction Networks
ABSTRACT Chromatin interactions play important roles in transcription regulation. To better understand the underlying evolutionary and functional constraints of these interactions, we implemented a systems approach to examine RNA polymerase-II-associated chromatin interactions in human cells. We found that 40% of the total genomic elements involved in chromatin interactions converged to a giant, scale-free-like, hierarchical network organized into chromatin communities. The communities were enriched in specific functions and were syntenic through evolution. Disease-associated SNPs from genome-wide association studies were enriched among the nodes with fewer interactions, implying their selection against deleterious interactions by limiting the total number of interactions, a model that we further reconciled using somatic and germline cancer mutation data. The hubs lacked disease-associated SNPs, constituted a nonrandomly interconnected core of key cellular functions, and exhibited lethality in mouse mutants, supporting an evolutionary selection that favored the nonrandom spatial clustering of the least-evolving key genomic domains against random genetic or transcriptional errors in the genome. Altogether, our analyses reveal a systems-level evolutionary framework that shapes functionally compartmentalized and error-tolerant transcriptional regulation of human genome in three dimensions.
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ABSTRACT: Recent studies uncovered important core/periphery network structures characterizing complex sets of cooperative and competitive interactions between network nodes, be they proteins, cells, species or humans. Better characterization of the structure, dynamics and function of core/periphery networks is a key step of our understanding cellular functions, species adaptation, social and market changes. Here we summarize the current knowledge of the structure and dynamics of "traditional" core/periphery networks, rich-clubs, nested, bow-tie and onion networks. Comparing core/periphery structures with network modules, we discriminate between global and local cores. The core/periphery network organization lies in the middle of several extreme properties, such as random/condensed structures, clique/star configurations, network symmetry/asymmetry, network assortativity/disassortativity, as well as network hierarchy/anti-hierarchy. These properties of high complexity together with the large degeneracy of core pathways ensuring cooperation and providing multiple options of network flow re-channelling greatly contribute to the high robustness of complex systems. Core processes enable a coordinated response to various stimuli, decrease noise, and evolve slowly. The integrative function of network cores is an important step in the development of a large variety of complex organisms and organizations. In addition to these important features and several decades of research interest, studies on core/periphery networks still have a number of unexplored areas.09/2013; 1(2). DOI:10.1093/comnet/cnt016
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ABSTRACT: The precise regulation of gene transcription during metazoan development is controlled by a complex system of interactions between transcription factors, histone modifications and modifying enzymes and chromatin conformation. Developments in chromosome conformation capture technologies have revealed that interactions between regions of chromatin are pervasive and highly cell-type specific. The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications. However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known. In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions. In addition, we review the insights into both local and global patterns of chromatin interactions that have been revealed by the latest experimental and computational methods.Nucleic Acids Research 06/2013; 41(15). DOI:10.1093/nar/gkt499 · 8.81 Impact Factor
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ABSTRACT: After the initial enthusiasm of the human genome project, it became clear that without additional data pertaining to the epigenome, i.e., how the genome is marked at specific developmental periods, in different tissues, as well as across individuals and species-the promise of the genome sequencing project in understanding biology cannot be fulfilled. This realization prompted several large-scale efforts to map the epigenome, most notably the Encyclopedia of DNA Elements (ENCODE) project. While there is essentially a single genome in an individual, there are hundreds of epigenomes, corresponding to various types of epigenomic marks at different developmental times and in multiple tissue types. Unprecedented advances in next-generation sequencing (NGS) technologies, by virtue of low cost and high speeds that continue to improve at a rate beyond what is anticipated by Moore's law for computer hardware technologies, have revolutionized molecular biology and genetics research, and have in turn prompted innovative ways to reduce the problem of measuring cellular events involving DNA or RNA into a sequencing problem. In this article, we provide a brief overview of the epigenome, the various types of epigenomic data afforded by NGS, and some of the novel discoveries yielded by the epigenomics projects. We also provide ample references for the reader to get in-depth information on these topics.03/2014; 12(1):2-11. DOI:10.5808/GI.2014.12.1.2