CTCF/cohesin-binding sites are frequently mutated in cancer

Katainen, Riku; Dave, Kashyap; Pitkänen, Esa; Palin, Kimmo; Kivioja, Teemu; Välimäki, Niko; Gylfe, Alexandra E.; Ristolainen, Heikki; Hänninen, Ulrika A.; Cajuso, Tatiana; Kondelin, Johanna; Tanskanen, Tomas; Mecklin∥, Jukka–Pekka; Järvinen, Heikki; Renkonen–Sinisalo, Laura; Lepistö, Anna; Kaasinen, Eevi; Kilpivaara, Outi; Tuupanen, Sari; Enge, Martin; Taipale, Jussi; Aaltonen, Lauri A.

doi:10.1038/ng.3335

Cited by 397 publications

(436 citation statements)

References 29 publications

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“…In general, the number of such mutations ranges from a few hundred (as found in some types of paediatric cancer) to more than a million (in hypermutator forms of colon and endometrial cancer) [98][99][100] . Oncogenic driver mutations in this category can be genetically identified by comparing their observed occurrence with that expected from the background mutation rate.…”

Section: Somatic Non-coding Mutations In Enhancersmentioning

confidence: 99%

“…As a consequence, the number of recurrent mutations in the non-coding genome that have been identified so far is small. For example, unbiased analysis of mutations in the whole genome of colorectal cancer and CLL cells easily picks up mutational hot spots in known oncogenes and tumour suppressor genes, but fails to identify large numbers of recurrently mutated non-coding elements 99,101 . These data indicate either that non-coding driver mutations are relatively rare in cancer or that they are spread across a large number of different regulatory elements.…”

Section: Somatic Non-coding Mutations In Enhancersmentioning

confidence: 99%

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The role of enhancers in cancer

2016

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Enhancer elements function as the logic gates of the genetic regulatory circuitry. One of their most important functions is the integration of extracellular signals with intracellular cell fate information to generate cell type-specific transcriptional responses. Mutations occurring in cancer often misregulate enhancers that normally control the signal-dependent expression of growth-related genes. This misregulation can result from trans-acting mechanisms, such as activation of the transcription factors or epigenetic regulators that control enhancer activity, or can be caused in cis by direct mutations that alter the activity of the enhancer or its target gene specificity. These processes can generate tumour type-specific super-enhancers and establish a 'locked' gene regulatory state that drives the uncontrolled proliferation of cancer cells. Here, we review the role of enhancers in cancer, and their potential as therapeutic targets.

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Section: Somatic Non-coding Mutations In Enhancersmentioning

confidence: 99%

Section: Somatic Non-coding Mutations In Enhancersmentioning

confidence: 99%

The role of enhancers in cancer

2016

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“…More generally, mutations in individual CTCF sites can lead to loss of binding and disruption of loop formation, with important consequences for disease susceptibility. CTCF-binding sites are major hot spots for mutations in the cancer genome (Katainen et al 2015), and oncogenes can be activated by mutations that disrupt CTCF binding at the boundaries of loop domains ).…”

Section: Dna Methylation and Ctcf Bindingmentioning

confidence: 99%

CTCF: making the right connections

2016

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The role of the zinc finger protein CTCF in organizing the genome within the nucleus is now well established. Widely separated sites on DNA, occupied by both CTCF and the cohesin complex, make physical contacts that create large loop domains. Additional contacts between loci within those domains, often also mediated by CTCF, tend to be favored over contacts between loci in different domains. A large number of studies during the past 2 years have addressed the questions: How are these loops generated? What are the effects of disrupting them? Are there rules governing large-scale genome organization? It now appears that the strongest and evolutionarily most conserved of these CTCF interactions have specific rules for the orientation of the paired CTCF sites, implying the existence of a nonequilibrium mechanism of generation. Recent experiments that invert, delete, or inactivate one of a mating CTCF pair result in major changes in patterns of organization and gene expression in the surrounding regions. What remain to be determined are the detailed molecular mechanisms for re-establishing loop domains and maintaining them after replication and mitosis. As recently published data show, some mechanisms may involve interactions with noncoding RNAs as well as protein cofactors. Many CTCF sites are also involved in other functions such as modulation of RNA splicing and specific regulation of gene expression, and the relationship between these activities and loop formation is another unanswered question that should keep investigators occupied for some time.

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“…TADs partition chromosomes into blocks of DNA at scales of hundreds of kilobases to megabases of DNA and are frequently bounded at inverted CTCF-binding sites, suggesting that CTCF-mediated loops comprise a major organizing principle for the genome (Cook and Gove 1992;Dekker and Heard 2015;Dekker and Misteli 2015;Dixon et al 2012;Guo et al 2015;Ji et al 2016;Pope et al 2014;Smith et al 2016;Tang et al 2015;Valton and Dekker 2016). CTCF and cohesin are enriched at TAD boundaries (Guo et al 2015;Ji et al 2016;Katainen et al 2015;Rao et al 2015;Sofueva et al 2013;Tang et al 2015;Xiao et al 2011;Zuin et al 2014). The requirement for inverted CTCF sites is perplexing (Guo et al 2015;Rao et al 2014;Rao et al 2015); loops occurring on this scale would be expected to include many statistical segments and therefore to be insensitive to CTCF-site orientation.…”

Section: Intranuclear Topology Topography and Cartographymentioning

confidence: 99%

Controlling gene expression by DNA mechanics: emerging insights and challenges

2016

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Transcription initiation is a major control point for the precise regulation of gene expression. Our knowledge of this process has been mainly derived from protein-centric studies wherein cis-regulatory DNA sequences play a passive role, mainly in arranging the protein machinery to coalesce at the transcription start sites of genes in a spatial and temporalspecific manner. However, this is a highly dynamic process in which molecular motors such as RNA polymerase II (RNAPII), helicases, and other transcription factors, alter the level of mechanical force in DNA, rather than simply a set of static DNA-protein interactions. The double helix is a fiber that responds to flexural and torsional stress, which if accumulated, can affect promoter output as well as change DNA and chromatin structure. The relationship between DNA mechanics and the control of early transcription initiation events has been under-investigated. Genomic techniques to display topological stress and conformational variation in DNA across the mammalian genome provide an exciting new insight on the role of DNA mechanics in the early stages of the transcription cycle. Without understanding how torsional and flexural stresses are generated, transmitted, and dissipated, no model of transcription will be complete and accurate.

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CTCF/cohesin-binding sites are frequently mutated in cancer

Cited by 397 publications

References 29 publications

The role of enhancers in cancer

The role of enhancers in cancer

CTCF: making the right connections

Controlling gene expression by DNA mechanics: emerging insights and challenges

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