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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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Citations
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Motif Disruption Domains Lead To Cancer Gene Expression RewiringPreprint
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Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundariesPreprint
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“When it comes to cancer, many studies have revealed that mutations of CTCF binding sites and disruptions of insulated structures could result in dysregulation of gene expression (6-8), an intrinsic property in cancer.”
Background3D genome evolution and reorganization in the Drosophila melanogaster species groupPreprint
Torosin, N. S., Anand, A., Golla, T. R., Cao, W., & Ellison, C. E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.09.033753 · Cited by 3
Chromatin topology and the timing of enhancer function at the hoxd locusPreprint
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“Boundary disruption has been linked to cancer, diseases of limb development or linked to triplet expansions (Flavahan et al., 2016; Hnisz et al., 2016; Lupianez et al., 2015; Sun et al., 2018).”
BackgroundReplication stress underlies genomic instability at CTCF/cohesin-binding sites in cancerPreprint
Faseela, E. E., Notani, D., & Sabarinathan, R. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.24.563697 · Cited by 3
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Gene regulatory networks linked to GABA signalling emerge as relevant for glioblastoma pathogenesisPreprint
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“…such as deletions, duplications, or inversions of DNA segments within the TADs could lead to aberrant gene expression ( Hnisz et al., 2016a ; Szabo et al., 2019 ; Ji et al., 2016 ; Lupiáñez et al., 2015 ; Hnisz et al., 2016b ; Rao et al., 2017 ; Ren and Dixon, 2015 ; Bianco et al., 2018 ).”
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Evolution of CTCF binding sites in the human genome
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Anchoring Chromatin Loops to Cancer
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Pediatric Sarcomas: The Next Generation of Molecular Studies
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3D epigenomics and 3D epigenopathies
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“3,53,89,90 These include chromosomal translocations, inversions, and deletions that bring previously distant regulatory elements into proximity or bypass normal regulatory boundaries (Figure 2A).”
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HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries
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Morphine Re-Arranges Chromatin Spatial Architecture of Primate Cortical Neurons
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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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