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

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.

• Authors: Ying Li, Ziwei Liao, Huacheng Luo, Aissa Benyoucef, Yuanyuan Kang, Qian Lai, Sinisa Dovat, Barbara Miller, Iouri Chepelev, Yangqiu Li, Keji Zhao, Marjorie Brand, Suming Huang
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 48 Issue 6 Pg. 3119-3133 (04 06 2020) ISSN: 1362-4962 [Electronic] England
• PMID: 32086528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• CCCTC-Binding Factor
• CTCF protein, human
• Chromatin
• DNA-Binding Proteins
• T-Cell Acute Lymphocytic Leukemia Protein 1
• TAL1 protein, human

Topics

• Binding Sites (genetics)
• CCCTC-Binding Factor (genetics)
• Carcinogenesis (genetics)
• Chromatin (genetics)
• DNA-Binding Proteins (genetics)
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation, Neoplastic
• Genome, Human (genetics)
• Histone Code (genetics)
• Humans
• Jurkat Cells
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, pathology)
• Protein Binding (genetics)
• T-Cell Acute Lymphocytic Leukemia Protein 1 (genetics)
• Transcription, Genetic (genetics)