Abstract
Microdeletions in noncoding boundary elements can activate proto-oncogenes in T-ALL.
Major finding: Microdeletions in noncoding boundary elements can activate proto-oncogenes in T-ALL.
Mechanism: Disruption of insulated loop boundaries allows regulatory elements outside the loop to activate oncogenes.
Impact: Insulated neighborhood disruption can activate oncogenes without alterations in the target locus.
Proto-oncogenes can be activated by multiple mechanisms, including alterations that bring enhancers into proximity to regulate its expression. Enhancers form DNA loops to interact with target genes, and are regulated within larger CTCF-cohesin–mediated loops, termed insulated neighborhoods. Hnisz, Weintraub, and colleagues hypothesized that disruption of the insulated neighborhoods might lead to aberrant activation of proto-oncogenes by enhancer elements typically found outside of the neighborhood. The Insulated neighborhoods were mapped in a T-cell acute lymphoblastic leukemia (T-ALL) cell line using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) to identify cohesin sites, as cohesin has been shown to identify insulated neighborhoods. The majority of genes known to be involved in promoting T-ALL, both active oncogenes and silent proto-oncogenes, were located within the identified insulated neighborhoods in the T-ALL cells. Several common T-ALL deletions were found to affect insulated neighborhood boundaries, including deletions in TAL1 and LMO2, and deletions overlapping the CTCF boundary site suggest that boundary disruption may allow control by regulatory elements outside the insulated neighborhood. Consistent with these findings, deletion of the TAL1 neighborhood boundary with CRISPR/Cas9 is sufficient to activate TAL1, and similar results were observed with deletion of the LMO2 boundary. Further, analysis of mutations in cancer genomes from the ICGC database indicates an enrichment of mutations at boundary CTCF sites, but not non-boundary CTCF sites, suggesting that disruption of insulated neighborhoods may activate oncogenes in other tumor types. Together, these findings highlight a mechanism by which proto-oncogenes can be activated through disruption of the insulated chromosome neighborhood boundary, leading to oncogene regulation by enhancers outside of the neighborhood, and this mechanism may occur across tumor types.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.