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Activation of proto-oncogenes by disruption of chromosome neighborhoods
Open accessAbstract
The spread of bad neighborhoods: Our genomes have complex three-dimensional (3D) arrangements that partition and regulate gene expression. Cancer cells frequently have their genomes grossly rearranged, disturbing this intricate 3D organization. Hnisz et al. show that the disruption of these 3D neighborhoods can bring oncogenes under the control of regulatory elements normally kept separate from them (see the Perspective by Wala and Beroukim). These novel juxtapositions can result in the inappropriate activation of oncogenes. Science , this issue p. 1454 ; see also p. 1398
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“While genetic perturbation of CTCF binding has been shown to result in misregulation of gene expression in various cell lines and cancer9–11,28”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [10]
In the citing paper
“Boundary disruption has recently been linked to cancer and diseases of limb development (Flavahan et al., 2016; Hnisz et al., 2016; Lupianez et al., 2015)”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Hnisz et al., 2016
In the citing paper
“Recent high-resolution Chromosome-Conformation-Capture sequencing studies have revealed that TAD boundaries are perturbed in rare human limb malformation diseases (Lupianez et al., 2015) and certain types of cancers (Flavahan et al., 2016; Hnisz et al., 2016), leading to enhancer miswiring and pathogenic disruption of gene expression.”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Hnisz et al., 2016
In the citing paper
“Several other studies have reported the deregulation of chromatin folding structures in different cancer types11,15,16.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [15]
In the citing paper
“In a dozen loci and in multiple cell types, CRISPR/Cas9 deletion of CTCF binding sites at the anchors of insulated neighborhoods have been shown to produce changes in the expression of genes within the neighborhoods and immediately adjacent to the deleted neighborhood boundary.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“Somatic mutations occur frequently and recurrently in the loop anchors of oncogene-containing Insulated neighborhoods in a variety of cancer cells (Figure 2E).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“Similarly, in T cell leukemia cells, ~90% of all enhancer or promoter-related DNA loops occur within insulated neighborhood boundaries (Hnisz et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“Silent proto-oncogenes typically occur within insulated neighborhoods and genetic modification of the neighborhood loop anchors can cause activation of these oncogenes (Flavahan et al., 2016; Hnisz et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“The vast majority of enhancer-gene interactions occur within insulated neighborhoods (Dowen et al., 2014; Hnisz et al., 2016; Ji et al., 2016; Phillips-Cremins et al., 2013).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“These observations are consistent with the idea that mutations that alter the loop anchor sites of oncogene-containing insulated neighborhoods make an important contribution to the misregulation of gene expression that is inherent to the cancer state (Flavahan et al., 2016; Hnisz et al., 2016; Katainen et al., 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“Furthermore, chromosomal rearrangements such as translocations or deletions which activate oncogenes also disrupt insulated neighborhoods around those genes without altering the sequence of the gene itself (Groschel et al., 2014; Hnisz et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
In the citing paper
“Studies on insulated neighborhoods have estimated that approximately 80% of neighborhood boundaries of shared by any two cell types (Hnisz et al., 2016; Ji et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2016
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Citations
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BackgroundSelf-citationCTCF-mediated functional chromatin interactome in pluripotent cells
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BackgroundRevisiting Global Gene Expression Analysis
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Self-citationCTCF physically links cohesin to chromatin
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“T-ALL deletion catalog and overlap analysis Deletions in T-ALL genomes were compiled from multiple studies (22, 26, 59, 60).”
MethodThe 3D genome in transcriptional regulation and pluripotency
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BackgroundMolecular Genetics of Acute Lymphoblastic Leukemia
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“A T-cell acute lymphoblastic leukemia (TALL) cell (Jurkat) was selected for these studies because key T-ALL oncogenes and genetic alterations are well-known (13, 14).”
BackgroundSite‐specific recombination of the tal‐1 gene is a common occurrence in human T cell leukemia.
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“Several patient deletions, however, retained the TAL1 promoter SCIENCE sciencemag.org 25 MARCH 2016 • VOL 351 ISSUE 6280 1455 TAL1 9 8 ChIA-PET interactions: 40k 10 kb CTCF H3K27Ac RNA-Seq 72 kb 9 8 ChIA-PET interactions: 40k 115 kb 10 kb CTCF H3K27Ac RNA-Seq LMO2 Insulated neighborhood: Insulated neighborhood: LMO2 C…”
BackgroundInfluentialKieffer-Kwon, K.-R., Tang, Z., Mathé, E. A., Qian, J., Sung, M., Li, G., Resch, W., Baek, S., Pruett, N. D., Grøntved, L., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.039 · Cited by 337
ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing
Li, G., Fullwood, M. J., Han, X., Mulawadi, F. H., Velkov, S., Vega, V. B., Ariyaratne, P. N., Mohamed, Y. B., Ooi, H.-S., Tennakoon, C., et al. (2010) · Genome biology · doi:10.1186/gb-2010-11-2-r22 · Cited by 323 · cited 3×
“pipeline was adapted from a previous report (8) and was recently developed based on multiple previous studies (15, 32, 39).”
MethodInfluentialGenetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions
Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.048 · Cited by 319 · cited 3×
“We have analyzed our ChIA-PET data using two analytical approaches: one that estimates the background contact frequency based on the genomic proximity bias (Mango pipeline) adapted from previous reports (24, 30, 40), and an analytical approach that estimates the background contact frequency based on the ligation frequ…”
BackgroundMethodSeitan, V. C., Faure, A. J., Zhan, Y., McCord, R. P., Lajoie, B. R., Ing-Simmons, E., Lenhard, B., Giorgetti, L., Heard, E., Fisher, A. G., et al. (2013) · Genome Research · doi:10.1101/gr.161620.113 · Cited by 318 · cited 3×
“at the CD3 and GATA3 loci (41, 42) (Table S2A-B).”
BackgroundSelf-citationRoss-Innes, C. S., Becq, J., Warren, A., Cheetham, R. K., Northen, H., O’Donovan, M., Malhotra, S., di Pietro, M., Ivakhno, S., He, M., et al. (2015) · Nature Genetics · doi:10.1038/ng.3357 · Cited by 293
Genome-wide map of regulatory interactions in the human genome
Heidari, N., Phanstiel, D. H., He, C., Grubert, F., Jahanbani, F., Kasowski, M., Zhang, M. Q., & Snyder, M. P. (2014) · Genome Research · doi:10.1101/gr.176586.114 · Cited by 278 · cited 2×
“A recent study noted that mutations in CTCF binding sites occur frequently in cancers (23), but it is unclear if mutations in boundaries are common as only a subset of CTCF sites form insulated neighborhoods (8, 10, 24).”
BackgroundExploring long-range genome interactions using the WashU Epigenome Browser
Zhou, X., Lowdon, R. F., Li, D., Lawson, H. A., Madden, P. A. F., Costello, J., & Wang, T. (2013) · Nature Methods · doi:10.1038/nmeth.2440 · Cited by 209
Analysis of long-range chromatin interactions using Chromosome Conformation Capture
Naumova, N., Smith, E. M., Zhan, Y., & Dekker, J. (2012) · Methods · doi:10.1016/j.ymeth.2012.07.022 · Cited by 183 · cited 1×
“Generation of 5C libraries 3C was performed with HindIII restriction enzyme as previously described with some minor modifications (34, 57).”
MethodSelf-citationVlierberghe, P. V., van Grotel, M., Beverloo, H. B., Lee, C., Helgason, T., Buijs-Gladdines, J. G. C. A. M., Passier, M., van Wering, E. R., Veerman, A. J. P., Kamps, W. A., et al. (2006) · Blood · doi:10.1182/blood-2006-04-019927 · Cited by 178 · cited 13×
“3G); a previous study proposed that deletion of cryptic repressors located in the deleted region enables activation of LMO2 (21).”
BackgroundInfluentialMechanisms of transcription factor deregulation in lymphoid cell transformation
O’Neil, J., & Look, A. T. (2007) · Oncogene · doi:10.1038/sj.onc.1210766 · Cited by 128 · cited 2×
“The LMO2 gene encodes a transcription factor that is overexpressed and oncogenic in some forms of T-ALL (14, 20).”
BackgroundMango: a bias-correcting ChIA-PET analysis pipeline
Phanstiel, D. H., Boyle, A. P., Heidari, N., & Snyder, M. P. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv336 · Cited by 114 · cited 5×
“Several computational pipelines have thus been developed to estimate background contact frequencies based on this “genomic proximity bias,” both for chromosome conformation capture data (35, 36) and ChIA-PET data (30, 37).”
BackgroundMethodInfluentialMy5C: web tools for chromosome conformation capture studies
Lajoie, B. R., van Berkum, N. L., Sanyal, A., & Dekker, J. (2009) · Nature Methods · doi:10.1038/nmeth1009-690 · Cited by 89 · cited 2×
“5C read mapping Sequencing data were obtained from both an Illumina MiSeq and an Illumina HiSeq 2000 machine and was processed by a custom pipeline to map and assemble 5C interactions, as previously described (55, 56).”
MethodSelf-citationWang, J., Li, J.-W., Wang, X.-C., Zheng, C., & Ma, W.-D. (2013) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2013.08.032 · Cited by 81 · cited 1×
“4G, 4H) the following evidence indicated activation of the genes in the cancer types the mutations were documented in: FGFR1 was found overexpressed in liver carcinoma in previous studies (70, 71).”
BackgroundA statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions
Paulsen, J., Rødland, E. A., Holden, L., Holden, M., & Hovig, E. J. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku738 · Cited by 61 · cited 1×
“Several computational pipelines have thus been developed to estimate background contact frequencies based on this “genomic proximity bias,” both for chromosome conformation capture data (35, 36) and ChIA-PET data (30, 37).”
MethodFrom cells to chromatin: Capturing snapshots of genome organization with 5C technology
Ferraiuolo, M. A., Sanyal, A., Naumova, N., Dekker, J., & Dostie, J. (2012) · Methods · doi:10.1016/j.ymeth.2012.10.011 · Cited by 55
Self-citationAn NK and T Cell Enhancer Lies 280 Kilobase Pairs 3′ to the Gata3 Structural Gene
Hosoya-Ohmura, S., Lin, Y.-H., Herrmann, M., Kuroha, T., Rao, A. U. K., Moriguchi, T., Lim, K.-C., Hosoya, T., & Engel, J. D. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05065-11 · Cited by 45 · cited 1×
“at the CD3 and GATA3 loci (41, 42) (Table S2A-B).”
BackgroundChromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL
Zhou, Y., Kurukuti, S., Saffrey, P., Vukovic, M., Michie, A. M., Strogantsev, R., West, A. G., & Vetrie, D. L. P. (2013) · Blood · doi:10.1182/blood-2013-02-483875 · Cited by 34
Kwon, J., Lee, N., Park, J. Y., Yu, Y. S., Kim, J. P., Shin, J. H., Kim, D., Joh, J., Kim, D. S., Choi, K. Y., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064260 · Cited by 19
Flagged first, then by citations
2 of the 73 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- 10.1016/0092-8674(91)90636-D · DOI
Cited by
Sorted by citations
Coactivator condensation at super-enhancers links phase separation and gene control
Sabari, B. R., Dall’Agnese, A., Boija, A., Klein, I. A., Coffey, E. L., Shrinivas, K., Abraham, B. J., Hannett, N. M., Zamudio, A. V., Manteiga, J. C., et al. (2018) · Science · doi:10.1126/science.aar3958 · Cited by 2,595
Self-citationHiGlass: web-based visual exploration and analysis of genome interaction maps
Kerpedjiev, P., Abdennur, N. A., Lekschas, F., McCallum, C., Dinkla, K., Strobelt, H., Luber, J. M., Ouellette, S., Azhir, A., Kumar, N., et al. (2018) · Genome biology · doi:10.1186/s13059-018-1486-1 · Cited by 2,430
Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G. (2017) · Cell · doi:10.1016/j.cell.2017.05.004 · Cited by 1,709
“This highlights the crucial role of boundaries in mediating the physical insulation of neighboring chromosome domains, with important implications for disease-causing chromosomal rearrangements in humans (Flavahan et al., 2016; Franke et al., 2016; Hnisz et al., 2016).”
Self-citationA Phase Separation Model for Transcriptional Control
Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K., & Sharp, P. A. (2017) · Cell · doi:10.1016/j.cell.2017.02.007 · Cited by 1,753
Self-citationEpigenetic plasticity and the hallmarks of cancer
Flavahan, W. A., Gaskell, E., & Bernstein, B. E. (2017) · Science · doi:10.1126/science.aal2380 · Cited by 1,340
“Indeed, frequentmutations of CTCFmotifs in the vicinity of oncogenes have been reported in colorectal, liver, and esophageal cancer (50, 51).”
Background
Metadata
- Authors
- Hnisz, D., Weintraub, A. S., Day, D. S., Valton, A.-L., Bak, R. O., Li, C. H., Goldmann, J., Lajoie, B. R., Fan, Z. P., Sigova, A. A., Reddy, J., Borges-Rivera, D., Lee, T. I., Jaenisch, R., Porteus, M. H., Dekker, J., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- University of Massachusetts Chan Medical School (US)
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hnisz, Denes
- Weintraub, Abraham S.
- Young, Richard A.
- ORCID
- Venue
- Science
- Published
- 2016-03-25
- Volume
- 351
- Issue
- 6280
- Pages
- 1454-1458
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4884612
- OpenAlex
- W2303393194
- Cited by
- 1,042
- References
- 73
- Citations by year
- 2026: 48 · 2025: 67 · 2024: 90 · 2023: 106 · 2022: 90 · 2021: 124 · 2020: 129 · 2019: 132 · 2018: 102 · 2017: 104 · 2016: 48
- FWCI
- 66.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- HAL (submittedVersion)
- Funders
- Austrian Science Fund (J3490)
- Ludwig Graduate Fellowship
- Laurie Kraus Lacob Faculty Scholar Award in Pediatric Translational Research
- Hyundai Hope on Wheels
- Danish Council for Independent Research, Medical Sciences
- Sapere Aude Research Talent (DFF-1331-00735B)
- National Human Genome Research Institute (R01 HG003143, U54 HG007010, U01 HG007910)
- National Cancer Institute (U54 CA193419)
- NIH (HG002668, CA109901, NS088538, MH104610, AI120766, U54 DK107980, U01 DA 040588)
- National Institute of General Medical Sciences (R01 GM 112720)
- National Institute of Allergy and Infectious Diseases (U01 R01 AI 117839)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- proto-oncogenes, oncogene activation, T-cell acute lymphoblastic leukemia, microdeletion, chromosome structure, cancer genetics, gene expression regulation
- MeSH terms
- Chromosome Aberrations, Chromosome Mapping, Humans, Mutation, Proto-Oncogenes, Translocation, Genetic, Transcriptional Activation, Gene Expression Regulation, Leukemic, Sequence Deletion, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, HEK293 Cells
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