Journal
NUCLEIC ACIDS RESEARCH
Volume 48, Issue 6, Pages 3119-3133Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa098
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Funding
- National Institutes of Health (NIH) [R01DK110108, R01CA204044]
- Four Diamonds Endowed Epigenetic and Gene Regulation Research Program
- Canadian Institutes of Health Research [MOP-343603]
- Intramural Research Program, the National Heart, Lung and Blood Institute, NIH
- NIH [R01CA204044]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL005801, ZIAHL006030] Funding Source: NIH RePORTER
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Aberrant activation of the TAL1 is associated with up to 60% of TALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemiaprone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.
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