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

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  • Vinjamur, Divya S.
    • Other Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University
  • Alhashem, Yousef N.
    • Other Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University
  • Mohamad, Safa F.
    • Other Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University
  • Amin, Parth
    • Other Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University
  • Williams, David C.
    • Affiliation: School of Medicine
    • Other Affiliation: Massey Cancer Center; Virginia Commonwealth University
  • Lloyd, Joyce A.
    • Other Affiliation: Massey Cancer Center; Virginia Commonwealth University
Abstract
  • 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 erythroid cells, which express both γ- and β-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 β-globin locus control region (LCR), and the β-globin promoter. There is very little KLF1 binding detectable at the γ-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 β- but not the γ-globin gene. The amount of KLF1 expression strongly positively correlates with β-globin mRNA and weakly positively correlates with BCL11A mRNA. With modest KLF1 knockdown, mimicking haploinsufficiency, γ-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 γ-globin mRNA in UCB erythroblasts. Therefore, the role of KLF1 in γ-globin regulation in fetal erythroblasts is complex, with both positive and negative facets. Furthermore, in UCB erythroblasts, diminished BCL11A is not sufficient to induce γ-globin in the absence of KLF1. These findings have implications for the manipulation of BCL11A and/or KLF1 to induce γ-globin for therapy of the β-hemoglobinopathies.
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  • Article
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  • In Copyright
Journal title
  • PloS One
Journal volume
  • 11
Journal issue
  • 2
Page start
  • e0146802
Language
  • English
ISSN
  • 1932-6203

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