Project description:CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops. In addition to insulation of euchromatin from heterochromatin, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in human cancer, resulting in deregulation of global gene expression by altered methylated genomic states. In contrast to these studies, we here describe that inactivation of CTCF can drives subtle and local genomic effects that elevates oncogene expression levels from driving chromosomal rearrangements. For T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are predominantly found in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that couples the TLX3 oncogene in the vicinity of the BCL11B enhancer. This unique entity has been associated with γδ-lineage development. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele, but unexpectedly drives higher levels of the TLX3 oncogene from the translocated allele. In line, Ctcf conditional knockout mice have reduced numbers of αβ T cells but increased numbers of γδ T cells, a phenotype identical to that of Bcl11b knockout mice and implying that CTCF is directly involved in the regulation of the BCL11B enhancer. We demonstrate that most TLX3-rearranged patients with heterozygous CTCF aberrations preserved single intervening CTCF bindings sites in the translocation breakpoint areas located in between the BCL11B enhancer and the TLX3 oncogene. These intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3 regulatory sequences. Using reverse genetics, we provide evidence that heterozygous inactivation of CTCF diminishes competitive loop formation in favor of high-affinity TLX3 promoter loops to BCL11B enhancer sequences formed among multiple convergent CTCF binding sites. This boosts oncogene expression levels and leukemia burden in T-ALL patients.

			Action	DRS
		Other
	SRR15505800_1.fastq.gz	Fastqsanger.gz
	SRR15505800_2.fastq.gz	Fastqsanger.gz
	SRR15505769_1.fastq.gz	Fastqsanger.gz
	SRR15505769_2.fastq.gz	Fastqsanger.gz

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Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia [HiC]

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