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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 regulates CD44 and CXCR3 in CD4+ T cells(a) T-bet protein expression in WT and Jmjd3 cKO CD44+ and CD44− CD4 SP thymocytes. (b) Percentage of CXCR3+ cells in CD4+ SP T cells from WT and Jmjd3 cKO mice (data expressed as mean + SD of three independent experiments, *p < 0.05, **p < 0.01). (c) Frequency of CD44 and CXCR3 in WT and Jmjd3 cKO CD4+ SP thymocytes. (d) Naïve CD4+ T cells (2 × 106) derived from WT and Jmjd3 cKO mice were i.v. injected into irradiated Rag2−/−γc−/− mice (n = 3 for each group). Ten days later, frequency of CD44+CXCR3+-expressing T cells isolated from splenocytes. (representative of three independent experiments,*p < 0.05, **p < 0.01 determined by Student's t-test).
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Figure 5: Jmjd3 regulates CD44 and CXCR3 in CD4+ T cells(a) T-bet protein expression in WT and Jmjd3 cKO CD44+ and CD44− CD4 SP thymocytes. (b) Percentage of CXCR3+ cells in CD4+ SP T cells from WT and Jmjd3 cKO mice (data expressed as mean + SD of three independent experiments, *p < 0.05, **p < 0.01). (c) Frequency of CD44 and CXCR3 in WT and Jmjd3 cKO CD4+ SP thymocytes. (d) Naïve CD4+ T cells (2 × 106) derived from WT and Jmjd3 cKO mice were i.v. injected into irradiated Rag2−/−γc−/− mice (n = 3 for each group). Ten days later, frequency of CD44+CXCR3+-expressing T cells isolated from splenocytes. (representative of three independent experiments,*p < 0.05, **p < 0.01 determined by Student's t-test).

Mentions: Since T-bet is a critical transcription factor for Th1 cell differentiation43, we next investigated Jmjd3 regulation of T-bet and its target genes. CD44 is expressed at an early stage in T cell development in the thymus, and is regulated by Jmjd342. Indeed, we found that CD44 expression was significantly decreased in Jmjd3-deficient ThN and Th1 cells, single-positive (SP) CD4+ thymocytes and splenocytes (Fig.2f, Supplementary Fig. 2). We further analyzed CD44low (CD44−) and CD44high (CD44+) CD4+ SP thymic T cell populations and determined T-bet expression by FACS analysis. T-bet protein was reduced in the Jmjd3-deficient CD44 high T cell population compared with the WT CD44 high T cell population, whereas little or no T-bet was detected in the WT or Jmjd3-deficient CD44low T cell population (Fig. 5a). Furthermore, we found downregulated CD44 and CXCR3 (T-bet target genes) expression, or fewer numbers of cells expressing CD44, in Jmjd3-deficient T cells compared with WT T cells (Fig. 5b, 5c). To validate our findings in vivo, CXCR3 and CD44 expression were determined in splenocytes isolated from Rag2−/−γc−/− mice injected with WT or Jmjd3 cKO naïve CD4+ T cells. Percentage of T cells, expressing both CXCR3 and CD44, was downregulated in Jmjd3-deficient T cells compared with WT T cells, (Fig. 5d). These findings suggest that Jmjd3 deletion reduces the expression of T-bet, CXCR3, and CD44 in CD4+ T cells, or Jmjd3-deficient T cells contain fewer cells expressing T-bet, CXCR3, and CD44.


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 regulates CD44 and CXCR3 in CD4+ T cells(a) T-bet protein expression in WT and Jmjd3 cKO CD44+ and CD44− CD4 SP thymocytes. (b) Percentage of CXCR3+ cells in CD4+ SP T cells from WT and Jmjd3 cKO mice (data expressed as mean + SD of three independent experiments, *p < 0.05, **p < 0.01). (c) Frequency of CD44 and CXCR3 in WT and Jmjd3 cKO CD4+ SP thymocytes. (d) Naïve CD4+ T cells (2 × 106) derived from WT and Jmjd3 cKO mice were i.v. injected into irradiated Rag2−/−γc−/− mice (n = 3 for each group). Ten days later, frequency of CD44+CXCR3+-expressing T cells isolated from splenocytes. (representative of three independent experiments,*p < 0.05, **p < 0.01 determined by Student's t-test).
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Related In: Results  -  Collection

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Figure 5: Jmjd3 regulates CD44 and CXCR3 in CD4+ T cells(a) T-bet protein expression in WT and Jmjd3 cKO CD44+ and CD44− CD4 SP thymocytes. (b) Percentage of CXCR3+ cells in CD4+ SP T cells from WT and Jmjd3 cKO mice (data expressed as mean + SD of three independent experiments, *p < 0.05, **p < 0.01). (c) Frequency of CD44 and CXCR3 in WT and Jmjd3 cKO CD4+ SP thymocytes. (d) Naïve CD4+ T cells (2 × 106) derived from WT and Jmjd3 cKO mice were i.v. injected into irradiated Rag2−/−γc−/− mice (n = 3 for each group). Ten days later, frequency of CD44+CXCR3+-expressing T cells isolated from splenocytes. (representative of three independent experiments,*p < 0.05, **p < 0.01 determined by Student's t-test).
Mentions: Since T-bet is a critical transcription factor for Th1 cell differentiation43, we next investigated Jmjd3 regulation of T-bet and its target genes. CD44 is expressed at an early stage in T cell development in the thymus, and is regulated by Jmjd342. Indeed, we found that CD44 expression was significantly decreased in Jmjd3-deficient ThN and Th1 cells, single-positive (SP) CD4+ thymocytes and splenocytes (Fig.2f, Supplementary Fig. 2). We further analyzed CD44low (CD44−) and CD44high (CD44+) CD4+ SP thymic T cell populations and determined T-bet expression by FACS analysis. T-bet protein was reduced in the Jmjd3-deficient CD44 high T cell population compared with the WT CD44 high T cell population, whereas little or no T-bet was detected in the WT or Jmjd3-deficient CD44low T cell population (Fig. 5a). Furthermore, we found downregulated CD44 and CXCR3 (T-bet target genes) expression, or fewer numbers of cells expressing CD44, in Jmjd3-deficient T cells compared with WT T cells (Fig. 5b, 5c). To validate our findings in vivo, CXCR3 and CD44 expression were determined in splenocytes isolated from Rag2−/−γc−/− mice injected with WT or Jmjd3 cKO naïve CD4+ T cells. Percentage of T cells, expressing both CXCR3 and CD44, was downregulated in Jmjd3-deficient T cells compared with WT T cells, (Fig. 5d). These findings suggest that Jmjd3 deletion reduces the expression of T-bet, CXCR3, and CD44 in CD4+ T cells, or Jmjd3-deficient T cells contain fewer cells expressing T-bet, CXCR3, and CD44.

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