Epigenetic activation of the foxa2 gene is required for maintaining the potential of neural precursor cells to differentiate into dopaminergic neurons after expansion

So Young Bang, So Hee Kwon, Sang Hoon Yi, Sang Ah Yi, Eun Kyung Park, Jae Cheol Lee, Choon Gon Jang, Jueng Soo You, Sang Hun Lee, Jeung Whan Han

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Dysregulation of forkhead box protein A2 (Foxa2) expression in fetal ventral mesencephalon (VM)-derived neural precursor cells (NPCs) appears to be associated with the loss of their potential to differentiate into dopaminergic (DA) neurons after mitogenic expansion in vitro, hindering their efficient use as a transplantable cell source. Here, we report that epigenetic activation of Foxa2 in VM-derived NPCs by inducing histone hyperacetylation rescues the mitogenic-expansion-dependent decrease of differentiation potential to DA neurons. The silencing of Foxa2 gene expression after expansion is accompanied by repressive histone modifications, including hypoacetylation of histone H3 and H4 and trimethylation of H3K27 on the Foxa2 promoter, as well as on the global level. In addition, histone deacetylase 7 (HDAC7) is highly expressed during differentiation and recruited to the Foxa2 promoter. Induction of histone acetylation in VM-derived NPCs by either knockdown of HDAC7 or treatment with the HDAC inhibitor apicidin upregulates Foxa2 expression via hyperacetylation of H3 and a decrease in H3K27 trimethylation on the promoter regions, leading to the expression of DA neuron developmental genes and enhanced differentiation of DA neurons. These effects are antagonized by the expression of shRNAs specific for Foxa2 but enhanced by shRNA for HDAC7. Collectively, these findings indicate that loss of differentiation potential of expanded VM-derived NPCs is attributed to a decrease in Foxa2 expression and suggest that activation of the endogenous Foxa2 gene by epigenetic regulation might be an approach to enhance the generation of DA neurons.

Original languageEnglish
Pages (from-to)520-533
Number of pages14
JournalStem Cells and Development
Volume24
Issue number4
DOIs
Publication statusPublished - 2015 Jan 1

Fingerprint

Dopaminergic Neurons
Epigenomics
Transcriptional Activation
Mesencephalon
Histones
Histone Deacetylases
Hepatocyte Nuclear Factor 3-beta
Histone Code
Developmental Genes
Histone Deacetylase Inhibitors
Acetylation
Genetic Promoter Regions
Small Interfering RNA
Up-Regulation
Gene Expression
Genes

All Science Journal Classification (ASJC) codes

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Bang, So Young ; Kwon, So Hee ; Yi, Sang Hoon ; Yi, Sang Ah ; Park, Eun Kyung ; Lee, Jae Cheol ; Jang, Choon Gon ; You, Jueng Soo ; Lee, Sang Hun ; Han, Jeung Whan. / Epigenetic activation of the foxa2 gene is required for maintaining the potential of neural precursor cells to differentiate into dopaminergic neurons after expansion. In: Stem Cells and Development. 2015 ; Vol. 24, No. 4. pp. 520-533.
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abstract = "Dysregulation of forkhead box protein A2 (Foxa2) expression in fetal ventral mesencephalon (VM)-derived neural precursor cells (NPCs) appears to be associated with the loss of their potential to differentiate into dopaminergic (DA) neurons after mitogenic expansion in vitro, hindering their efficient use as a transplantable cell source. Here, we report that epigenetic activation of Foxa2 in VM-derived NPCs by inducing histone hyperacetylation rescues the mitogenic-expansion-dependent decrease of differentiation potential to DA neurons. The silencing of Foxa2 gene expression after expansion is accompanied by repressive histone modifications, including hypoacetylation of histone H3 and H4 and trimethylation of H3K27 on the Foxa2 promoter, as well as on the global level. In addition, histone deacetylase 7 (HDAC7) is highly expressed during differentiation and recruited to the Foxa2 promoter. Induction of histone acetylation in VM-derived NPCs by either knockdown of HDAC7 or treatment with the HDAC inhibitor apicidin upregulates Foxa2 expression via hyperacetylation of H3 and a decrease in H3K27 trimethylation on the promoter regions, leading to the expression of DA neuron developmental genes and enhanced differentiation of DA neurons. These effects are antagonized by the expression of shRNAs specific for Foxa2 but enhanced by shRNA for HDAC7. Collectively, these findings indicate that loss of differentiation potential of expanded VM-derived NPCs is attributed to a decrease in Foxa2 expression and suggest that activation of the endogenous Foxa2 gene by epigenetic regulation might be an approach to enhance the generation of DA neurons.",
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Epigenetic activation of the foxa2 gene is required for maintaining the potential of neural precursor cells to differentiate into dopaminergic neurons after expansion. / Bang, So Young; Kwon, So Hee; Yi, Sang Hoon; Yi, Sang Ah; Park, Eun Kyung; Lee, Jae Cheol; Jang, Choon Gon; You, Jueng Soo; Lee, Sang Hun; Han, Jeung Whan.

In: Stem Cells and Development, Vol. 24, No. 4, 01.01.2015, p. 520-533.

Research output: Contribution to journalArticle

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T1 - Epigenetic activation of the foxa2 gene is required for maintaining the potential of neural precursor cells to differentiate into dopaminergic neurons after expansion

AU - Bang, So Young

AU - Kwon, So Hee

AU - Yi, Sang Hoon

AU - Yi, Sang Ah

AU - Park, Eun Kyung

AU - Lee, Jae Cheol

AU - Jang, Choon Gon

AU - You, Jueng Soo

AU - Lee, Sang Hun

AU - Han, Jeung Whan

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AB - Dysregulation of forkhead box protein A2 (Foxa2) expression in fetal ventral mesencephalon (VM)-derived neural precursor cells (NPCs) appears to be associated with the loss of their potential to differentiate into dopaminergic (DA) neurons after mitogenic expansion in vitro, hindering their efficient use as a transplantable cell source. Here, we report that epigenetic activation of Foxa2 in VM-derived NPCs by inducing histone hyperacetylation rescues the mitogenic-expansion-dependent decrease of differentiation potential to DA neurons. The silencing of Foxa2 gene expression after expansion is accompanied by repressive histone modifications, including hypoacetylation of histone H3 and H4 and trimethylation of H3K27 on the Foxa2 promoter, as well as on the global level. In addition, histone deacetylase 7 (HDAC7) is highly expressed during differentiation and recruited to the Foxa2 promoter. Induction of histone acetylation in VM-derived NPCs by either knockdown of HDAC7 or treatment with the HDAC inhibitor apicidin upregulates Foxa2 expression via hyperacetylation of H3 and a decrease in H3K27 trimethylation on the promoter regions, leading to the expression of DA neuron developmental genes and enhanced differentiation of DA neurons. These effects are antagonized by the expression of shRNAs specific for Foxa2 but enhanced by shRNA for HDAC7. Collectively, these findings indicate that loss of differentiation potential of expanded VM-derived NPCs is attributed to a decrease in Foxa2 expression and suggest that activation of the endogenous Foxa2 gene by epigenetic regulation might be an approach to enhance the generation of DA neurons.

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