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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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In the citing paper
“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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Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma
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Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia
Kloetgen, A., Thandapani, P., Ntziachristos, P., Ghebrechristos, Y. E., Nomikou, S., Lazaris, C., Chen, X., Hu, H., Bakogianni, S., Wang, J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0602-9 · Cited by 219
“Frequent loss of TAD boundary insulation has been previously observed in human cancer, including T-ALL 49 .”
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DeepC: predicting 3D genome folding using megabase-scale transfer learning
Schweßinger, R., Gosden, M. E., Downes, D. J., Brown, R. C., Oudelaar, A. M., Telenius, J. M., Teh, Y. W., Lunter, G. A., & Hughes, J. R. (2020) · Nature Methods · doi:10.1038/s41592-020-0960-3 · Cited by 223
“…E u r op e P M C F und e r s A u t ho r M a nu s c r i p t s E u r op e P M C F und e r s A u t ho r M a nu s c r i p t s kb CRISPR-mediated deletion in HEK293T cells, encompassing four CTCF sites at the LMO2 locus, leads to a local rearrangement of the chromatin structure as confirmed by 5C 31 .”
BackgroundMethodInfluentialCuartero, S., Weiss, F. D., Dharmalingam, G., Guo, Y., Ing-Simmons, E., Masella, S., Robles-Rebollo, I., Xiao, X., Wang, Y.-F., Barozzi, I., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0184-1 · Cited by 210
Hallmarks of cancer—the new testament
Senga, S. S., & Grose, R. P. (2021) · Open Biology · doi:10.1098/rsob.200358 · Cited by 245
“Verhaak R et al. 2010 Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.”
BackgroundInfluentialDNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner
Collins, P. L., Purman, C. E., Porter, S. I., Nganga, V. K., Saini, A., Hayer, K. E., Gurewitz, G. L., Sleckman, B. P., Bednarski, J. J., Bassing, C. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16926-x · Cited by 231
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer
Johnstone, S. E., Reyes, A., Qi, Y., Adriaens, C., Hegazi, E., Pelka, K., Chen, J. H., Zou, L.-L., Drier, Y., Hecht, V. C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.030 · Cited by 189
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CRISPR off-target analysis in genetically engineered rats and mice
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“If the repair of DNA damage disrupts a TAD boundary, enhancers and promoters that are normally segregated may become juxtaposed, causing misregulation of oncogenes (Hnisz et al. 2016).”
BackgroundLandscape of cohesin-mediated chromatin loops in the human genome
Grubert, F., Srivas, R., Spacek, D. V., Kasowski, M. M., Ruiz-Velasco, M., Sinnott-Armstrong, N., Greenside, P., Narasimha, A. M., Liu, Q., Geller, B. S., et al. (2020) · Nature · doi:10.1038/s41586-020-2151-x · Cited by 203
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Circulating tumor cells: from new biological insights to clinical practice
Gu, X., Wei, S., & Lv, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01938-6 · Cited by 204
“403 The proto-oncogene TAL1 is activated by microdeletions that obliterate TAD boundaries in T-ALL.”
BackgroundCTCF-mediated topological boundaries during development foster appropriate gene regulationPreprint
Narendra, V. K., Bulajić, M., Dekker, J., Mazzoni, E. O., & Reinberg, D. (2016) · Genes & Development · doi:10.1101/gad.288324.116 · Cited by 178
“Relocating a gene or genomic segment from one side of a topological boundary to the other dramatically changes its regulatory associations and thus transcriptional output (Hnisz et al. 2016; Neijts et al. 2016).”
Self-citationThe Epigenetic Hallmarks of Cancer
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Position effects influence HIV latency reversal
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Targeting transcription cycles in cancer
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Topologically associating domain boundaries are required for normal genome function
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“…by the overall depletion of structural variants at TAD boundaries observed in the general human population 26 , while disruptions and rearrangements of TAD structure have been implicated in the mis-expression of genes and are associated with developmental and cancer phenotypes 1 – 3, 29, 30 .”
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Independence of chromatin conformation and gene regulation during Drosophila dorsoventral patterning
Ing-Simmons, E., Vaid, R., Bing, X. Y., Levine, M., Mannervik, M., & Vaquerizas, J. M. (2021) · Nature Genetics · doi:10.1038/s41588-021-00799-x · Cited by 159
Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions
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Self-citationHiCcompare: an R-package for joint normalization and comparison of HI-C datasets
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Aberrant Super‐Enhancer Landscape in Human Hepatocellular Carcinoma
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Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements
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Beagan, J. A., Pastuzyn, E. D., Fernandez, L. R., Guo, M. H., Feng, K., Titus, K. R., Chandrashekar, H., Shepherd, J. D., & Phillips-Cremins, J. E. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0634-6 · Cited by 143
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Genome control by SMC complexes
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CTCF sites display cell cycle–dependent dynamics in factor binding and nucleosome positioningPreprint
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“We investigated the same regions as previously described and we used the same primer pool (Hnisz et al. 2016).”
InfluentialSelf-citationGenetic–epigenetic interactions in cis: a major focus in the post-GWAS era
Do, C., Shearer, A., Suzuki, M., Terry, M. B., Gelernter, J. E., Greally, J. M., & Tycko, B. (2017) · Genome biology · doi:10.1186/s13059-017-1250-y · Cited by 145
Developing in 3D: the role of CTCF in cell differentiation
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“…Eukaryotic chromosomes are organized in the three-dimensional (3D) nuclear space and this folding is important for processes such as DNA replication, repair, recombination and transcription (Franke et al., 2016; Hnisz et al., 2016; Hu et al., 2015; Lupiáñez et al., 2015; Pope et al., 2014).”
BackgroundAcute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping
Hyle, J. W., Zhang, Y., Wright, S., Xu, B., Shao, Y., Easton, J. B., Tian, L., Feng, R., Xu, P., & Li, C. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz462 · Cited by 132
Self-citationA critical assessment of topologically associating domain prediction tools
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Amaral, P., Leonardi, T., Han, N., Viré, E. A., Gascoigne, D. K., Arias‐Carrasco, R., Büscher, M., Pandolfini, L., Zhang, A., Pluchino, S., et al. (2018) · Genome biology · doi:10.1186/s13059-018-1405-5 · Cited by 136
“Finally, considering the recent involvement of CTCF and architectural mutations in activation of oncogenes in specific tumours [58, 59], which represent hitherto overlooked potential causative mutations, we performed a mutational analysis of CTCF motifs associated with tapRNA loci.”
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LADL: light-activated dynamic looping for endogenous gene expression control
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Radiation-induced DNA damage and repair effects on 3D genome organization
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Pediatric T‐cell acute lymphoblastic leukemia
Karrman, K., & Johansson, B. (2016) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22416 · Cited by 136
“…chromosomal structures, and long-range chromatin interactions (Janssen et al., 1993; Mansour et al., 2014; Patel et al., 2014; Navarro et al., 2015; Hnisz et al., 2016), LMO2 by 11p12-13 deletions (Van Vlierberghe et al., 2006), TLX3 by a translocation to BCL11B (MacLeod et al., 2003), MYB by gene…”
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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