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, Anindita Basak, Stuart H. Orkin, Jian Xu and Vijay G. Sankaran ()
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Yong Shen: Harvard Medical School
Jeffrey M. Verboon: Harvard Medical School
Yuannyu Zhang: University of Texas Southwestern Medical Center
Nan Liu: Harvard Medical School
Yoon Jung Kim: University of Texas Southwestern Medical Center
Samantha Marglous: Harvard Medical School
Satish K. Nandakumar: Harvard Medical School
Richard A. Voit: Harvard Medical School
Claudia Fiorini: Harvard Medical School
Ayesha Ejaz: Harvard Medical School
Anindita Basak: Harvard Medical School
Stuart H. Orkin: Harvard Medical School
Jian Xu: University of Texas Southwestern Medical Center
Vijay G. Sankaran: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25298-9

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