CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia.

Blood
Huacheng LuoS Huang

Abstract

HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene-expression patterns within confined chromatin domains for normal development. Here, we used targeted pooled CRISPR-Cas9-knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci. We discovered that the CTCF binding site located between HOXA7 and HOXA9 genes (CBS7/9) is critical for establishing and maintaining aberrant HOXA9-HOXA13 gene expression in AML. Disruption of the CBS7/9 boundary resulted in spreading of repressive H3K27me3 into the posterior active HOXA chromatin domain that subsequently impaired enhancer/promoter chromatin accessibility and disrupted ectopic long-range interactions among the posterior HOXA genes. Consistent with the role of the CBS7/9 boundary in HOXA locus chromatin organization, attenuation of the CBS7/9 boundary function reduced posterior HOXA gene expression and altered myeloid-specific transcriptome profiles important for pathogenesis of myeloid malignancies. Fur...Continue Reading

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Citations

Sep 8, 2019·Nature Communications·Josh TyckoMichael C Bassik
Jan 12, 2019·International Journal of Hematology·Lorenzo BrunettiMargaret A Goodell
Jul 22, 2020·Leukemia·Celestia FangPanagiotis Ntziachristos
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Jul 29, 2021·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Sadik CigdemMitsuru Okuwaki
Nov 8, 2021·The FEBS Journal·Sajesan AryalRui Lu

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