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Kruppel-Like Transcription Factor KLF1 Is Required for Optimal ?- and ?-Globin Expression in Human Fetal Erythroblasts.

ABSTRACT: In human adult erythroid cells, lower than normal levels of Krüppel-like transcription factor 1 (KLF1) are generally associated with decreased adult ?- and increased fetal ?-globin gene expression. KLF1 also regulates BCL11A, a known repressor of adult ?-globin expression. In seeming contrast to the findings in adult cells, lower amounts of KLF1 correlate with both reduced embryonic and reduced fetal ?-like globin mRNA in mouse embryonic erythroid cells. The role of KLF1 in primary human fetal erythroid cells, which express both ?- and ?-globin mRNA, is less well understood. Therefore, we studied the role of KLF1 in ex vivo differentiated CD34+ umbilical cord blood cells (UCB erythroblasts), representing the fetal milieu. In UCB erythroblasts, KLF1 binds to the ?-globin locus control region (LCR), and the ?-globin promoter. There is very little KLF1 binding detectable at the ?-globin promoter. Correspondingly, when cultured fetal UCB erythroblasts are subjected to lentiviral KLF1 knockdown, the active histone mark H3K4me3 and RNA pol II recruitment are diminished at the ?- but not the ?-globin gene. The amount of KLF1 expression strongly positively correlates with ?-globin mRNA and weakly positively correlates with BCL11A mRNA. With modest KLF1 knockdown, mimicking haploinsufficiency, ?-globin mRNA is increased in UCB erythroblasts, as is common in adult cells. However, a threshold level of KLF1 is evidently required, or there is no absolute increase in ?-globin mRNA in UCB erythroblasts. Therefore, the role of KLF1 in ?-globin regulation in fetal erythroblasts is complex, with both positive and negative facets. Furthermore, in UCB erythroblasts, diminished BCL11A is not sufficient to induce ?-globin in the absence of KLF1. These findings have implications for the manipulation of BCL11A and/or KLF1 to induce ?-globin for therapy of the ?-hemoglobinopathies.

SUBMITTER: Vinjamur DS

PROVIDER: S-EPMC4739742 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Krüppel-Like Transcription Factor KLF1 Is Required for Optimal γ- and β-Globin Expression in Human Fetal Erythroblasts.

Vinjamur Divya S DS Alhashem Yousef N YN Mohamad Safa F SF Amin Parth P Williams David C DC Lloyd Joyce A JA

PloS one 20160203 2

In human adult erythroid cells, lower than normal levels of Krüppel-like transcription factor 1 (KLF1) are generally associated with decreased adult β- and increased fetal γ-globin gene expression. KLF1 also regulates BCL11A, a known repressor of adult γ-globin expression. In seeming contrast to the findings in adult cells, lower amounts of KLF1 correlate with both reduced embryonic and reduced fetal β-like globin mRNA in mouse embryonic erythroid cells. The role of KLF1 in primary human fetal e ...[more]

PMID: 26840243

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Project description:The etiology and severity of anemia, a common blood disorder, are diverse. Dominant mutations in Krüppel-like factor 1 (KLF1/EKLF) underlie the molecular basis for some of them. KLF1 is a zinc finger transcription factor that plays an essential role in red blood cell proliferation and differentiation. Mutations have been identified in the KLF1 gene that cause hematologic diseases. Two of these alter one allele but generate an extreme phenotype: the mouse Nan mutation (E339D) leads to hemolytic neonatal anemia with hereditary spherocytosis, and the human CDA mutation (E325K) causes congenital dyserythropoietic anemia (CDA) type IV. These modify functionally important amino acids in the zinc finger DNA-binding domain at positions involved in direct interactions with regulatory elements of KLF1's target genes. Although the two dominant mutations alter the same evolutionarily conserved glutamic acid residue, the substitutions are not equivalent and lead to divergent consequences for the molecular mechanisms underlying activity of these mutants, particularly in recognition and interaction with their unique binding sites. Consequently, the properties of the protein are transformed such that it acquires novel dominant characteristics whose effects may not be limited to the erythroid compartment. KLF1 mutants cause loss-of-function/haploinsufficiency effects on some KLF1 wild-type target genes, while at the same time gain-of-function effects activate ectopic sites and neomorphic gene expression. Such anomalies not only lead to intrinsic red cell problems, but also to expression of non-erythroid genes that systemically disturb organ development. This review highlights recent molecular, biochemical, and genetic studies of KLF1 mutants, particularly the dramatic consequences that come from just a single amino acid change. The study of these variants provides an important contribution to the overall understanding of the DNA-protein interface of the zinc finger subtype of transcription factors, and the potential clinical consequences of what might appear to be a minor change in sequence.

Dataset Information

Kruppel-Like Transcription Factor KLF1 Is Required for Optimal ?- and ?-Globin Expression in Human Fetal Erythroblasts.

Publications

Krüppel-Like Transcription Factor KLF1 Is Required for Optimal γ- and β-Globin Expression in Human Fetal Erythroblasts.

Similar Datasets

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