Activation of proto-oncogenes by disruption of chromosome neighborhoods

By Denes Hnisz, A. Weintraub, Daniel S. Day, Anne-Laure Valton, R. Bak, Charles H. Li, Johanna E. Goldmann, B. Lajoie, Z. Fan, A. Sigova and 7 more. Science, 2015

954 citations recorded by the source corpus.

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 Disrupting the boundaries between three-dimensional neighborhoods in the genome can activate cancer-promoting genes. [Also see Perspective by Wala and Beroukim] Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d290f977586fac98c695346c9591e33763269987

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Citations in the corpus

Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization (2017, neutral): “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).”
Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, background): “…important developmental genes are positioned and regulated at such boundaries (Fabre et al., 2015) and these structures can be especially implicated in developmental diseases and cancer (Hnisz et al., 2016; Ibn-Salem et al., 2014; Katainen et al., 2015; Lupianez et al., 2015; Maass et al., 2012).”
Transcriptional Addiction in Cancer (2017, neutral): “Thus, the CTCF DNA-binding motif in loop anchor regions is among the most altered human transcription factor-binding sequences in cancer cells (Hnisz et al., 2016b; Ji et al., 2016; Katainen et al., 2015).”
High-resolution TADs reveal DNA sequences underlying genome organization in flies (2017, background): “Interestingly, mutations of the CTCF binding motif at TAD boundaries are particularly abundant in cancer, causing dysregulation of oncogenes (Hnisz et al. 2016).”
The chromatin accessibility landscape of primary human cancers (2018, background): “However, these mutations were relatively rare and often had only small effects on the accessibility of the CTCF motif site despite a known enrichment of somatic mutations in CTCF motif sites in cancer (51, 52).”
YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, neutral): “Insulators: Insulators were defined by downloading the called insulated neighborhoods from (Hnisz et al., 2016a) (available at: http://younglab. wi.mit.edu/ insulatedneighborhoods.htm).”
Epigenetic plasticity and the hallmarks of cancer (2017, background): “Indeed, frequentmutations of CTCFmotifs in the vicinity of oncogenes have been reported in colorectal, liver, and esophageal cancer (50, 51).”