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Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis.

CTCF 相关染色质邻域的改变抑制 TAL1-driven 致癌转录程序和白血病发生。

  • 影响因子:11.14
  • DOI:10.1093/nar/gkaa098
  • 作者列表:"Li Y","Liao Z","Luo H","Benyoucef A","Kang Y","Lai Q","Dovat S","Miller B","Chepelev I","Li Y","Zhao K","Brand M","Huang S
  • 发表时间:2020-02-22
Abstract

:Aberrant activation of the TAL1 is associated with up to 60% of T-ALL 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 leukemia-prone 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.

摘要

: TAL1 的异常激活与高达 60% 的 T-ALL 病例相关,并参与 TAL1 位点内 CTCF 介导的基因组组织, 提示 CTCF 边界在 T-ALL 中起致病作用。在这里,我们发现-31-Kb CTCF 结合位点 (-31CBS) 作为染色质边界,定义了 TAL1 激活所需的拓扑结合域 (TAD) 和增强子/启动子相互作用。删除或倒置-31CBS 以上下文依赖的方式损害 TAL1 表达。缺失-31CBS 降低染色质可及性,阻断 + 51 红系增强子与 TAL1 启动子-1 之间的长程相互作用,导致抑制红系细胞中 TAL1 的表达, 但不是 T-ALL 细胞。然而,在 T-ALL 细胞 TAL1-expressing, 易患白血病的 TAL1 启动子-IV 与位于 TAL1 下游 19kb 的 + 19 干细胞增强子特异性相互作用,这种相互作用被 T-ALL 细胞中的-31CBS 倒置破坏。Jurkat 细胞中-31CBS 的倒置改变染色质可及性、组蛋白修饰和 CTCF 介导的 TAD,导致 TAL1 表达抑制和白血病发生 TAL1-driven。因此,我们的数据揭示了-31CBS 作为关键调节因子来定义 T-ALL 中 + 19-增强子和白血病倾向启动子 IV 相互作用 TAL1 激活。操纵 CTCF 边界可改变白血病发生中的 TAL1 TAD 和致癌转录网络。

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影响因子:6.50
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