A unified model of human hemoglobin switching through single-cell genome editing
| Autor: | Nan Liu, Jian Xu, Stuart H. Orkin, Anindita Basak, Claudia Fiorini, Samantha Marglous, Vijay G. Sankaran, Satish K. Nandakumar, Yoon Jung Kim, Yuannyu Zhang, Richard A. Voit, Ayesha Ejaz, Yong Shen, Jeffrey M. Verboon |
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| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities HBG1 Science General Physics and Astronomy Gene Expression Locus (genetics) Human genetic variation Computational biology beta-Globins Biology General Biochemistry Genetics and Molecular Biology Chromosomes Article Hemoglobins Genome editing hemic and lymphatic diseases Fetal hemoglobin Humans Erythropoiesis Transcription factor Fetal Hemoglobin Gene Editing Multidisciplinary Sickle cell disease Promoter General Chemistry Chromatin Globins Gene regulation DNA-Binding Proteins Repressor Proteins Mutation CRISPR-Cas Systems Transcription Factors |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Genetic mechanisms underlying fetal hemoglobin (HbF) regulation and switching are not fully understood. Here, the authors develop a single-cell genome editing functional assay to model how effects of mutation-harbouring functional elements contribute to HbF expression. |
| Databáze: | OpenAIRE |
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