Author:
Gnanapragasam M. N.,Planutis A.,Glassberg J. A.,Bieker J. J.
Abstract
AbstractThe onset of erythropoiesis is under strict developmental control, with direct and indirect inputs influencing its derivation from the hematopoietic stem cell. A major regulator of this transition is KLF1/EKLF, a zinc finger transcription factor that plays a global role in all aspects of erythropoiesis. Here, we have identified a short, conserved enhancer element in KLF1 intron 1 that is important for establishing optimal levels of KLF1 in mouse and human cells. Chromatin accessibility of this site exhibits cell-type specificity and is under developmental control during the differentiation of human CD34+ cells towards the erythroid lineage. This site binds GATA1, SMAD1, TAL1, and ETV6. In vivo editing of this region in cell lines and primary cells reduces KLF1 expression quantitatively. However, we find that, similar to observations seen in pedigrees of families with KLF1 mutations, downstream effects are variable, suggesting that the global architecture of the site is buffered towards keeping the KLF1 genetic region in an active state. We propose that modification of intron 1 in both alleles is not equivalent to complete loss of function of one allele.
Funder
Cooley's Anemia Foundation
Doris Duke Charitable Foundation
National Institute of Diabetes and Digestive and Kidney Diseases
Publisher
Springer Science and Business Media LLC
Reference114 articles.
1. Laurenti, E. & Gottgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature (London) 553, 418–426 (2018).
2. Miller, I. J. & Bieker, J. J. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins. Mol. Cell. Biol. 13, 2776–2786 (1993).
3. Perkins, A. et al. Kruppeling erythropoiesis: An unexpected broad spectrum of human red blood cell disorders due to KLF1 variants. Blood 127, 1856–1862 (2016).
4. Waye, J. S. & Eng, B. Kruppel-like factor 1: Hematologic phenotypes associated with KLF1 gene mutations. Int. J. Lab. Hematol. 37(Suppl 1), 78–84 (2015).
5. Gnanapragasam, M. N. & Bieker, J. J. Orchestration of late events in erythropoiesis by KLF1/EKLF. Curr. Opin. Hematol. 24, 183–190 (2017).
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