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Nat Commun DOI:10.1038/s41467-021-25298-9

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

Publication TypeJournal Article
Year of Publication2021
AuthorsShen, Y, Verboon, JM, Zhang, Y, Liu, N, Kim, YJung, Marglous, S, Nandakumar, SK, Voit, RA, Fiorini, C, Ejaz, A, Basak, A, Orkin, SH, Xu, J, Sankaran, VG
JournalNat Commun
Date Published2021 08 17

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.


Alternate JournalNat Commun
PubMed ID34404810
Grant ListR56 DK125234 / DK / NIDDK NIH HHS / United States
R01 DK103794 / DK / NIDDK NIH HHS / United States
R01 HL146500 / HL / NHLBI NIH HHS / United States
R01 CA230631 / CA / NCI NIH HHS / United States
R01 DK111430 / DK / NIDDK NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States