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

Huacheng Luo, Fei Wang, Jie Zha, Haoli Li, Bowen Yan, Qinghua Du, Fengchun Yang, Amin Sobh, Christopher Vulpe, Leylah Drusbosky, Christopher Cogle, Iouri Chepelev, Bing Xu, Stephen D. Nimer, Jonathan Licht, Yi Qiu, Baoan Chen, Mingjiang Xu, Suming Huang

Research output: Contribution to journalArticle

3 Citations (Scopus)

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. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.

Original languageEnglish (US)
Pages (from-to)837-848
Number of pages12
JournalBlood
Volume132
Issue number8
DOIs
StatePublished - Aug 23 2018

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Transcription
Acute Myeloid Leukemia
Gene expression
Chromatin
Genes
Gene Expression
Heterografts
Clustered Regularly Interspaced Short Palindromic Repeats
Myeloid Cells
Nuclear Proteins
Transcriptome
Protein Binding
Neoplasms
Screening
Binding Sites
Survival
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Luo, Huacheng ; Wang, Fei ; Zha, Jie ; Li, Haoli ; Yan, Bowen ; Du, Qinghua ; Yang, Fengchun ; Sobh, Amin ; Vulpe, Christopher ; Drusbosky, Leylah ; Cogle, Christopher ; Chepelev, Iouri ; Xu, Bing ; Nimer, Stephen D. ; Licht, Jonathan ; Qiu, Yi ; Chen, Baoan ; Xu, Mingjiang ; Huang, Suming. / CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. In: Blood. 2018 ; Vol. 132, No. 8. pp. 837-848.
@article{7a674bf29bc14558a9ce7acea39e255a,
title = "CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia",
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. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.",
author = "Huacheng Luo and Fei Wang and Jie Zha and Haoli Li and Bowen Yan and Qinghua Du and Fengchun Yang and Amin Sobh and Christopher Vulpe and Leylah Drusbosky and Christopher Cogle and Iouri Chepelev and Bing Xu and Nimer, {Stephen D.} and Jonathan Licht and Yi Qiu and Baoan Chen and Mingjiang Xu and Suming Huang",
year = "2018",
month = "8",
day = "23",
doi = "10.1182/blood-2017-11-814319",
language = "English (US)",
volume = "132",
pages = "837--848",
journal = "Blood",
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Luo, H, Wang, F, Zha, J, Li, H, Yan, B, Du, Q, Yang, F, Sobh, A, Vulpe, C, Drusbosky, L, Cogle, C, Chepelev, I, Xu, B, Nimer, SD, Licht, J, Qiu, Y, Chen, B, Xu, M & Huang, S 2018, 'CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia', Blood, vol. 132, no. 8, pp. 837-848. https://doi.org/10.1182/blood-2017-11-814319

CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. / Luo, Huacheng; Wang, Fei; Zha, Jie; Li, Haoli; Yan, Bowen; Du, Qinghua; Yang, Fengchun; Sobh, Amin; Vulpe, Christopher; Drusbosky, Leylah; Cogle, Christopher; Chepelev, Iouri; Xu, Bing; Nimer, Stephen D.; Licht, Jonathan; Qiu, Yi; Chen, Baoan; Xu, Mingjiang; Huang, Suming.

In: Blood, Vol. 132, No. 8, 23.08.2018, p. 837-848.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia

AU - Luo, Huacheng

AU - Wang, Fei

AU - Zha, Jie

AU - Li, Haoli

AU - Yan, Bowen

AU - Du, Qinghua

AU - Yang, Fengchun

AU - Sobh, Amin

AU - Vulpe, Christopher

AU - Drusbosky, Leylah

AU - Cogle, Christopher

AU - Chepelev, Iouri

AU - Xu, Bing

AU - Nimer, Stephen D.

AU - Licht, Jonathan

AU - Qiu, Yi

AU - Chen, Baoan

AU - Xu, Mingjiang

AU - Huang, Suming

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.

AB - 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. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.

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U2 - 10.1182/blood-2017-11-814319

DO - 10.1182/blood-2017-11-814319

M3 - Article

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SP - 837

EP - 848

JO - Blood

JF - Blood

SN - 0006-4971

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