Activation of proto-oncogenes by disruption of chromosome neighborhoods

Hnisz, Denes; Weintraub, Abraham S.; Day, Daniel S.; Valton, Anne‐Laure; Bak, Rasmus O.; Li, Charles Han; Goldmann, Johanna; Lajoie, Bryan R.; Fan, Zi Peng; Sigova, Alla A.; Reddy, Josina C.; Borges-Rivera, Diego; Lee, Tong Ihn; Jaenisch, Rudolf; Porteus, Matthew H.; Dekker, Job; Young, Richard A.

doi:10.1126/science.aad9024

Cited by 936 publications

(955 citation statements)

References 71 publications

(52 reference statements)

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“…Within this hierarchical organization, conserved TAD and sub-TAD structures frame the majority of enhancer-promoter interactions (Dekker et al 2013;Tang et al 2015;Dekker and Mirny 2016). The CCCTCbinding factor (CTCF) regulates each nested level of genomic organization (Guo et al 2015;Hnisz et al 2016), from local enhancer-promoter looping events within the protocadherin clusters to broader genomic neighborhoods and TADs (Guo et al 2012;Rao et al 2014).…”

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confidence: 99%

CTCF-mediated topological boundaries during development foster appropriate gene regulation

et al. 2016

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The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development.

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confidence: 99%

CTCF-mediated topological boundaries during development foster appropriate gene regulation

et al. 2016

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“…During leukemic development, healthy hematopoietic cells switch from normal to enhanced transcription by increasing the number of super- or stretched-enhancers at promoter or enhancer elements. Subsequently, new chromatin loop structures form that change topologically associated domains, which trigger reprogramming of cancer cells [1,2]. We are starting to gain insights into organized chromatin regulatory circuits that not only contain proteins and DNA, but also structural or regulatory RNA, to promote oncogenic gene transcription [3].…”

Section: Introductionmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…In the case of heterochromatin, which is transcriptionally repressed, organization can be explained by phase separation (Larson et al, 2017;Strom et al, 2017). For euchromatin, the transcriptionally permissive part of chromatin, spatial organization is required in development and health (Lupiáñez et al, 2015;Flavahan et al, 2016;Hnisz et al, 2016;Symmons et al, 2016), but a mechanism of euchromatin organization has not yet been described.…”

Section: Introductionmentioning

confidence: 99%

Transcription organizes euchromatin similar to an active microemulsion

Hilbert

Sato

Kimurâ

et al. 2017

Preprint

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Graphical abstract HighlightsThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/234112 doi: bioRxiv preprint first posted online Dec. 15, 2017; Page 2 of 46 SummaryThe three-dimensional organization of the genome is essential for development and health. Although the organization of euchromatin (transcriptionally permissive chromatin) dynamically adjusts to changes in transcription, the underlying mechanisms remain elusive. Here, we studied how transcription organizes euchromatin, using experiments in zebrafish embryonic cells and theory. We show that transcription establishes an interspersed pattern of chromatin domains and RNA-enriched microenvironments. Specifically, accumulation of RNA in the vicinity of transcription sites creates microenvironments that locally remodel chromatin by displacing not transcribed chromatin. Ongoing transcriptional activity stabilizes the interspersed pattern of chromatin domains and RNA-enriched microenvironments by establishing contacts between chromatin and RNA. We explain our observations with an active microemulsion model based on two macromolecular mechanisms: RNA/RNA-binding protein complexes generally segregate from chromatin, while transcribed chromatin is retained among RNA/RNA-binding protein accumulations. We propose that microenvironments might be central to genome architecture and serve as gene regulatory hubs.

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Activation of proto-oncogenes by disruption of chromosome neighborhoods

Cited by 936 publications

References 71 publications

CTCF-mediated topological boundaries during development foster appropriate gene regulation

CTCF-mediated topological boundaries during development foster appropriate gene regulation

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Transcription organizes euchromatin similar to an active microemulsion

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