Abstract
CCCTC-binding factor (CTCF) can both activate as well as inhibit transcription by forming chromatin loops between regulatory regions and promoters. In this regard, Ctcf binding on non-methylated DNA and its interaction with the Cohesin complex results in differential regulation of the H19/Igf2 locus. Similarly, a role for CTCF has been established in normal hematopoietic development; however its involvement in leukemia remains elusive. Here, we show that Ctcf binds to the imprinting control region of H19/Igf2 in AML blasts. We also demonstrate that Smarca5, which also associates with the Cohesin complex, facilitates Ctcf binding to its target sites on DNA. Furthermore, Smarca5 supports Ctcf functionally and is needed for enhancer-blocking effect at ICR. We next asked whether CTCF and SMARCA5 control the expression of key hematopoiesis regulators. In normally differentiating myeloid cells both CTCF and SMARCA5 together with members of the Cohesin complex are recruited to the SPI1 gene, a key hematopoiesis regulator and leukemia suppressor. Due to DNA methylation, CTCF binding to the SPI1 gene is blocked in AML blasts. Upon AZA-mediated DNA demethylation of human AML blasts, CTCF and SMARCA5 are recruited to the −14.4 Enhancer of SPI1 gene and block its expression. Our data provide new insight into complex SPI1 gene regulation now involving additional key epigenetic factors, CTCF and SMARCA5 that control PU.1 expression at the −14.4 Enhancer.
Highlights
Control of tumor suppressor gene expression requires cooperation of epigenetic factors and represents crucial yet not fully understood events in leukemogenesis
Our work demonstrates an important role for a CTCF/ SMARCA5 interaction in the regulation of gene expression in acute myeloid leukemia (AML) by showing cooperating activities of CTCF and SMARCA5 on the SPI1 gene in AML blasts
We described the role of ATP-dependent chromatin remodeling factor Smarca5 during the process of Ctcf-imprinting control region (ICR) interaction
Summary
Control of tumor suppressor gene expression requires cooperation of epigenetic factors and represents crucial yet not fully understood events in leukemogenesis. Ctcf is a key epigenetic regulator and zinc-finger transcription factor, whose binding to DNA can be prevented by DNA methylation [1]. Ctcf regulates the well-established imprinted H19/Igf locus by blocking communication between the Igf promoter and its enhancer leading to increased transcription of H19 on the maternal allele. Ctcf association within a cohesin complex at the H19/Igf locus enables long-range chromatin interactions [2] and efficient enhancer blocking [3] on the unmethylated imprinting control region (ICR) of the maternal allele [4]. The mechanisms by which Ctcf regulates these processes are not well understood
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