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      Revisiting 3D chromatin architecture in cancer development and progression

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      Nucleic Acids Research
      Oxford University Press

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          Abstract

          Cancer development and progression are demarcated by transcriptional dysregulation, which is largely attributed to aberrant chromatin architecture. Recent transformative technologies have enabled researchers to examine the genome organization at an unprecedented dimension and precision. In particular, increasing evidence supports the essential roles of 3D chromatin architecture in transcriptional homeostasis and proposes its alterations as prominent causes of human cancer. In this article, we will discuss the recent findings on enhancers, enhancer–promoter interaction, chromatin topology, phase separation and explore their potential mechanisms in shaping transcriptional dysregulation in cancer progression. In addition, we will propose our views on how to employ state-of-the-art technologies to decode the unanswered questions in this field. Overall, this article motivates the study of 3D chromatin architecture in cancer, which allows for a better understanding of its pathogenesis and develop novel approaches for diagnosis and treatment of cancer.

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          Most cited references133

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position.

            We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.
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              Landscape of transcription in human cells

              Summary Eukaryotic cells make many types of primary and processed RNAs that are found either in specific sub-cellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic sub-cellular localizations are also poorly understood. Since RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modifications and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations taken together prompt to a redefinition of the concept of a gene.
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                Author and article information

                Contributors
                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                04 November 2020
                17 September 2020
                17 September 2020
                : 48
                : 19
                : 10632-10647
                Affiliations
                Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford , Oxford OX3 7LD, U.K
                Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford , Oxford OX3 7LD, U.K
                Author notes
                To whom correspondence should be addressed. Tel: +44 1865226492; Email: siim.pauklin@ 123456ndorms.ox.ac.uk
                Author information
                http://orcid.org/0000-0001-8079-3837
                Article
                gkaa747
                10.1093/nar/gkaa747
                7641747
                32941624
                16e3c8ad-1be6-4e6b-842a-84e72d254095
                © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 September 2020
                : 21 August 2020
                : 02 July 2020
                Page count
                Pages: 16
                Funding
                Funded by: Cancer Research UK, DOI 10.13039/501100000289;
                Award ID: C59392/A25064
                Funded by: Royal Society, DOI 10.13039/501100000288;
                Funded by: Clarendon Fund, DOI 10.13039/501100014748;
                Funded by: St Edmund Hall Scholarship, UK;
                Award ID: SFF1920_CB_MSD_759707
                Categories
                AcademicSubjects/SCI00010
                Survey and Summary

                Genetics
                Genetics

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