| RRC ID |
77304
|
| 著者 |
Shen Y, Verboon JM, Zhang Y, Liu N, Kim YJ, Marglous S, Nandakumar SK, Voit RA, Fiorini C, Ejaz A, Basak A, Orkin SH, Xu J, Sankaran VG.
|
| タイトル |
A unified model of human hemoglobin switching through single-cell genome editing.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
12(1)
|
| ページ |
4991
|
| 公開日 |
2021-8-17
|
| DOI |
10.1038/s41467-021-25298-9
|
| PII |
10.1038/s41467-021-25298-9
|
| PMID |
34404810
|
| PMC |
PMC8371164
|
| MeSH |
CRISPR-Cas Systems
Chromatin
Chromosomes
DNA-Binding Proteins / metabolism
Fetal Hemoglobin / genetics
Fetal Hemoglobin / metabolism
Gene Editing*
Gene Expression
Globins
Hemoglobins / genetics*
Hemoglobins / metabolism*
Humans
Mutation
Repressor Proteins
Transcription Factors / metabolism
beta-Globins / genetics
|
| IF |
12.121
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
