Evidence map›Paper›PMID 34404810›Full record

ArticleNature communications2021

A unified model of human hemoglobin switching through single-cell genome editing.

Yong Shen, Jeffrey M Verboon, Yuannyu Zhang, Nan Liu, Yoon Jung Kim, Samantha Marglous, Satish K Nandakumar, Richard A Voit, Claudia Fiorini, Ayesha Ejaz and 4 more

Open access · goldAbstract read
In one paragraph

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
3.7field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 31 citations in OpenAlex.

  1. Article
  2. Review
  3. Mechanisms of Globin Gene Regulation in Mammals.Annual review of genetics · 2025
    Review
  4. Characterization of diverse Cas9 orthologs for genome and epigenome editing.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  5. Article
  6. Transcriptional regulators of fetal hemoglobin.Hematology, transfusion and cell therapy · 2024
    Review
  7. Article
  8. Article
  9. Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2024
    Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. LRF Promotes Indirectly Advantageous Chromatin Conformation viaInternational journal of molecular sciences · 2022
    Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 1 country.

Yong ShenDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jeffrey M VerboonDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Yuannyu ZhangChildren's Medical Center Research Institute, Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nan LiuDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-8314-0900
Yoon Jung KimChildren's Medical Center Research Institute, Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Samantha MarglousDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Satish K NandakumarDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-7853-426X
Richard A VoitDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Claudia FioriniDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-4878-2438
Ayesha EjazDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Anindita BasakDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-7046-4500
Stuart H OrkinDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jian XuChildren's Medical Center Research Institute, Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID 0000-0003-1988-7337
Vijay G SankaranDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.ORCID 0000-0003-0044-443X
Broad Institute · USChildren's Medical Center · USBoston Children's Hospital · US

Funding

Stem Cell and Transplantation BiologyU54DK106829 · NIDDK · FRED HUTCHINSON CANCER RESEARCH CENTER · PI DEREK L STIREWALT · 2015 to 2026
$9.1M
MOLECULAR ANALYSIS OF NORMAL AND TYHALASSEMIC DNAR01HL032259 · NHLBI · CHILDREN'S HOSPITAL BOSTON · PI ORKIN, STUART H · 1985 to 2022
$8.8M
Systematic Genetic Dissection of Human ErythropoiesisR01DK103794 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2014 to 2026
$5.9M
Next generation functional genomics of hematology traitsR01HL146500 · NHLBI · UNIVERSITY OF WASHINGTON · PI ALEXANDER P REINER · 2020 to 2026
$5.7M
Molecular Analysis of Transcriptional Enhancers in HematopoiesisR01DK111430 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI Jian Xu · 2016 to 2026
$4.8M
Targeting Metabolic Liabilities of Leukemia-Initiating Cells (R01CA230631)R01CA230631 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI XU, JIAN · 2019 to 2023
$1.8M
Integrating Human Genetics and Single-Cell Functional Assays to Elucidate Mechanisms of Fetal Hemoglobin RegulationR56DK125234 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI SANKARAN, VIJAY GANESH · 2020 to 2020
$312k
Howard Hughes Medical InstituteNCI NIH HHS R01 CA230631NHLBI NIH HHS R01 HL032259NHLBI NIH HHS R01 HL146500NIDDK NIH HHS R01 DK103794NIDDK NIH HHS R01 DK111430NIDDK NIH HHS R56 DK125234NIDDK NIH HHS U54 DK106829
6 · The paper itself

Abstract

Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.

Indexed as

Gene Editingbeta-GlobinsChromatinChromosomesCRISPR-Cas SystemsDNA-Binding ProteinsFetal HemoglobinGene ExpressionGlobinsHemoglobinsHumansMutationRepressor ProteinsTranscription FactorsBCL11A protein, humanbeta-GlobinsChromatinDNA-Binding ProteinsFetal HemoglobinGlobinsHemoglobinsRepressor ProteinsTranscription FactorsZBTB7A protein, human

Identifiers

PMID34404810
PMCPMC8371164
OpenAlexW3195095735

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.