Three fingers on the switch: Kruppel-like factor 1 regulation of gamma-globin to beta-globin gene switching

Tallack, Michael R. and Perkins, Andrew C. (2013) Three fingers on the switch: Kruppel-like factor 1 regulation of gamma-globin to beta-globin gene switching. Current Opinion in Hematology, 20 3: 193-200. doi:10.1097/MOH.0b013e32835f59ba


Author Tallack, Michael R.
Perkins, Andrew C.
Title Three fingers on the switch: Kruppel-like factor 1 regulation of gamma-globin to beta-globin gene switching
Formatted title
Three fingers on the switch: Krüppel-like factor 1 regulation of γ-globin to β-globin gene switching
Journal name Current Opinion in Hematology   Check publisher's open access policy
ISSN 1065-6251
1531-7048
Publication date 2013-05-01
Year available 2013
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1097/MOH.0b013e32835f59ba
Open Access Status Not Open Access
Volume 20
Issue 3
Start page 193
End page 200
Total pages 8
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
Purpose of Review: Krüppel-like factor 1 (KLF1) regulates most aspects of erythropoiesis. Many years ago, transgenic mouse studies implicated KLF1 in the control of the human γ-globin to β-globin switch. In this review, we will integrate these initial studies with recent developments in human genetics to discuss our present understanding of how KLF1 and its target genes direct the switch.

Recent Findings: Recent studies have shown that human mutations in KLF1 are common and mostly asymptomatic, but lead to significant increases in levels of fetal hemoglobin (HbF) (α2γ2) and adult HbA2 (α2δ2). Genome-wide association studies (GWAS) have demonstrated that three primary loci are associated with increased HbF levels in the population: the β-globin locus itself, the BCL11A locus, and a site between MYB and HBS1L. We discuss evidence that KLF1 directly regulates BCL11A, MYB and other genes, which are involved directly or indirectly in γ-globin silencing, thus providing a link between GWAS and KLF1 in hemoglobin switching.

Summary: KLF1 regulates the γ-globin to β-globin genetic switch by many mechanisms. Firstly, it facilitates formation of an active chromatin hub (ACH) at the β-globin gene cluster. Specifically, KLF1 conscripts the adult-stage β-globin gene to replace the γ-globin gene within the ACH in a stage-specific manner. Secondly, KLF1 acts as a direct activator of genes that encode repressors of γ-globin gene expression. Finally, KLF1 is a regulator of many components of the cell cycle machinery. We suggest that dysregulation of these genes leads to cell cycle perturbation and 'erythropoietic stress' leading to indirect upregulation of HbF.
Keyword Active chromatin hub
BCL11A
Cell cycle
Kruppel-like factor 1
MYB
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID DP0770471/ACP
APP1030143
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
 
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