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Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation.

Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, Wang HY, Wang RF - Nat Commun (2014)

Bottom Line: The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines.H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors.Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA.

ABSTRACT
Epigenetic factors have been implicated in the regulation of CD4(+) T-cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T-cell differentiation remains unknown. Here we report that Jmjd3 ablation promotes CD4(+) T-cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T-cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

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Jmjd3 functionally regulates gene expression and DNA-binding(a) Ectopically expressed Jmjd3 rescues the gene expression in Jmjd3-deficient T cells. (b, c) Ectopically expressed Jmjd3 enhances the binding of the transcription factors, T-bet and Smad3, to their target genes (*p < 0.05). (d) Schematic diagram illustrating the proposed mechanistic role of Jmjd3 in the regulation of CD4+ T cell differentiation. Jmjd3 interacts with T-bet-RbBP5 and Ash2L to form a stable complex with transcription factors capable of binding to target gene promoters, thus allowing Jmjd3 to alter H3K327 methylation and Ash2L/RbBP5 to alter H3K4 levels to control target gene expression. Jmjd3 upregulates the expression of Th1 and Treg cell differentiation factors, including Foxp3, Ifng, Cd44, and Cxcr3, and downregulates the expression of the Th2 cell differentiation factors Rorc and Gata3. These changes in gene expression lead to the promotion of Th1 and Treg cell differentiation and the inhibition of Th2 and Th17 cell differentiation.
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Figure 8: Jmjd3 functionally regulates gene expression and DNA-binding(a) Ectopically expressed Jmjd3 rescues the gene expression in Jmjd3-deficient T cells. (b, c) Ectopically expressed Jmjd3 enhances the binding of the transcription factors, T-bet and Smad3, to their target genes (*p < 0.05). (d) Schematic diagram illustrating the proposed mechanistic role of Jmjd3 in the regulation of CD4+ T cell differentiation. Jmjd3 interacts with T-bet-RbBP5 and Ash2L to form a stable complex with transcription factors capable of binding to target gene promoters, thus allowing Jmjd3 to alter H3K327 methylation and Ash2L/RbBP5 to alter H3K4 levels to control target gene expression. Jmjd3 upregulates the expression of Th1 and Treg cell differentiation factors, including Foxp3, Ifng, Cd44, and Cxcr3, and downregulates the expression of the Th2 cell differentiation factors Rorc and Gata3. These changes in gene expression lead to the promotion of Th1 and Treg cell differentiation and the inhibition of Th2 and Th17 cell differentiation.

Mentions: To further validate the functional significance of the physical interactions between Jmjd3 and the transcription factors, we ectopically expressed Jmjd3 in CD4+ T cells under different cytokine conditions. Ectopic expression of Jmjd3 rescued transcription factor and target gene expression (Fig. 8a, Supplementary Fig. 7). ChIP-qPCR analysis revealed that Jmjd3 expression also rescued the binding of the T-bet to Cxcr3, Ifng, and Cd44 promoter regions, and restored the binding of Smad3 to the Foxp3 promoter (Fig. 8b,8c). Taken together, our results indicate that Jmjd3 regulates T cell differentiation by interacting with specific transcription and epigenetic factors.


Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation.

Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, Wang HY, Wang RF - Nat Commun (2014)

Jmjd3 functionally regulates gene expression and DNA-binding(a) Ectopically expressed Jmjd3 rescues the gene expression in Jmjd3-deficient T cells. (b, c) Ectopically expressed Jmjd3 enhances the binding of the transcription factors, T-bet and Smad3, to their target genes (*p < 0.05). (d) Schematic diagram illustrating the proposed mechanistic role of Jmjd3 in the regulation of CD4+ T cell differentiation. Jmjd3 interacts with T-bet-RbBP5 and Ash2L to form a stable complex with transcription factors capable of binding to target gene promoters, thus allowing Jmjd3 to alter H3K327 methylation and Ash2L/RbBP5 to alter H3K4 levels to control target gene expression. Jmjd3 upregulates the expression of Th1 and Treg cell differentiation factors, including Foxp3, Ifng, Cd44, and Cxcr3, and downregulates the expression of the Th2 cell differentiation factors Rorc and Gata3. These changes in gene expression lead to the promotion of Th1 and Treg cell differentiation and the inhibition of Th2 and Th17 cell differentiation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4274750&req=5

Figure 8: Jmjd3 functionally regulates gene expression and DNA-binding(a) Ectopically expressed Jmjd3 rescues the gene expression in Jmjd3-deficient T cells. (b, c) Ectopically expressed Jmjd3 enhances the binding of the transcription factors, T-bet and Smad3, to their target genes (*p < 0.05). (d) Schematic diagram illustrating the proposed mechanistic role of Jmjd3 in the regulation of CD4+ T cell differentiation. Jmjd3 interacts with T-bet-RbBP5 and Ash2L to form a stable complex with transcription factors capable of binding to target gene promoters, thus allowing Jmjd3 to alter H3K327 methylation and Ash2L/RbBP5 to alter H3K4 levels to control target gene expression. Jmjd3 upregulates the expression of Th1 and Treg cell differentiation factors, including Foxp3, Ifng, Cd44, and Cxcr3, and downregulates the expression of the Th2 cell differentiation factors Rorc and Gata3. These changes in gene expression lead to the promotion of Th1 and Treg cell differentiation and the inhibition of Th2 and Th17 cell differentiation.
Mentions: To further validate the functional significance of the physical interactions between Jmjd3 and the transcription factors, we ectopically expressed Jmjd3 in CD4+ T cells under different cytokine conditions. Ectopic expression of Jmjd3 rescued transcription factor and target gene expression (Fig. 8a, Supplementary Fig. 7). ChIP-qPCR analysis revealed that Jmjd3 expression also rescued the binding of the T-bet to Cxcr3, Ifng, and Cd44 promoter regions, and restored the binding of Smad3 to the Foxp3 promoter (Fig. 8b,8c). Taken together, our results indicate that Jmjd3 regulates T cell differentiation by interacting with specific transcription and epigenetic factors.

Bottom Line: The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines.H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors.Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA.

ABSTRACT
Epigenetic factors have been implicated in the regulation of CD4(+) T-cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T-cell differentiation remains unknown. Here we report that Jmjd3 ablation promotes CD4(+) T-cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T-cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

Show MeSH
Related in: MedlinePlus