3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression

  1. Pamela Himadewi
  2. Xue Qing David Wang
  3. Fan Feng
  4. Haley Gore
  5. Yushuai Liu
  6. Lei Yu
  7. Ryo Kurita
  8. Yukio Nakamura
  9. Gerd P Pfeifer
  10. Jie Liu  Is a corresponding author
  11. Xiaotian Zhang  Is a corresponding author
  1. Van Andel Institute, United States
  2. The University of Michigan, United States
  3. Japanese Red Cross Society, Japan
  4. RIKEN BioResource Center, Japan

Abstract

Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named Hereditary Persistence of Fetal Hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3' end of the β-globin locus, including a CTCF binding site termed 3'HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3'HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE160425.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Pamela Himadewi

    Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xue Qing David Wang

    Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fan Feng

    The University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Haley Gore

    Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yushuai Liu

    Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lei Yu

    The University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ryo Kurita

    Research and Development Department Central Blood Institute Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Yukio Nakamura

    Cell Engineering Division, RIKEN BioResource Center, Ibaraki, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Gerd P Pfeifer

    Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5080-9604
  10. Jie Liu

    The University of Michigan, Ann Arbor, United States
    For correspondence
    drjieliu@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  11. Xiaotian Zhang

    The University of Michigan, Ann Arbor, United States
    For correspondence
    xiaozhan@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9533-4761

Funding

National Human Genome Research Institute (1R35HG011279-01)

  • Jie Liu

Van Andel Research Institute (Fellow program)

  • Xiaotian Zhang

American Society of Hematology (Scholar Program)

  • Xiaotian Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael D Bulger, University of Rochester, United States

Version history

  1. Preprint posted: May 18, 2021 (view preprint)
  2. Received: May 21, 2021
  3. Accepted: September 22, 2021
  4. Accepted Manuscript published: September 29, 2021 (version 1)
  5. Version of Record published: October 8, 2021 (version 2)

Copyright

© 2021, Himadewi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Pamela Himadewi
  2. Xue Qing David Wang
  3. Fan Feng
  4. Haley Gore
  5. Yushuai Liu
  6. Lei Yu
  7. Ryo Kurita
  8. Yukio Nakamura
  9. Gerd P Pfeifer
  10. Jie Liu
  11. Xiaotian Zhang
(2021)
3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression
eLife 10:e70557.
https://doi.org/10.7554/eLife.70557

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https://doi.org/10.7554/eLife.70557