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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 deletion alters CD4+ T cell populations in different organsFrequency of CD4+ T cell populations isolated from (a) small intestine, (b) spleen, (c) LN, and (d) colon of WT and Jmjd3 cKO mice (e) Frequency of thymic and splenic nTreg cell populations (CD25+CD4+GFP+) from WT and Jmjd3 cKO Foxp3-GFP reporter mice. Mean percentage of the indicated T cell populations ± SD shown as histograms (right panel)(representative of three independent experiments, n = 3 for each group, *p < 0.05 determined by Student's t-test).
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Figure 1: Jmjd3 deletion alters CD4+ T cell populations in different organsFrequency of CD4+ T cell populations isolated from (a) small intestine, (b) spleen, (c) LN, and (d) colon of WT and Jmjd3 cKO mice (e) Frequency of thymic and splenic nTreg cell populations (CD25+CD4+GFP+) from WT and Jmjd3 cKO Foxp3-GFP reporter mice. Mean percentage of the indicated T cell populations ± SD shown as histograms (right panel)(representative of three independent experiments, n = 3 for each group, *p < 0.05 determined by Student's t-test).

Mentions: Recent studies have shown that Jmjd3 interacts with T-bet, a master transcription factor in Th1 cell differentiation, in a histone demethylase activity-independent manner39,40. However, the in vivo function of Jmjd3 in T cell differentiation remains unknown. To address this, we used fluorescence-activated cell sorting (FACS) analysis to determine the percentages of CD4+ T cell subsets in lymphocytes isolated from small intestine, spleen, lymph node (LN), and colon of wild-type (WT) and Jmjd3 cKO mice. Compared with WT mice, IFN-γ-producing Th1 cells were slightly increased in the LN and colon in Jmjd3 cKO mice, but decreased in the small intestine and spleen. IL-4-producing Th2 cells were increased in the small intestine and colon, but not significantly changed in spleen or LN (Fig. 1a-d). The percentage of IL-17-producing Th17 cells was substantially higher in the small intestines of Jmjd3 cKO mice compared with WT mice (14.8% vs. 3.8%) and in the colons (17.5% vs. 5.2%) of Jmjd3 cKO mice compared with WT mice (Fig. 1a,d). We did not observe any appreciable changes in lymphatic Th17 cells between WT and Jmjd3 cKO mice (Fig. 1c). Foxp3-expressing Treg cells were slightly higher in the small intestine, spleen, and LN (Fig. 1a-c), but not in the colon of Jmjd3 cKO mice compared with WT mice. To determine the effects of Jmjd3 on thymic and splenic natural Treg (nTreg) cell populations, WT and Jmjd3 cKO Foxp3-GFP reporter mice were generated. FACS analysis revealed that the percentage of thymic GFP+ nTreg cells was approximately 50% lower in Jmjd3 cKO mice than in WT mice. In contrast, the splenic nTreg cell population percentage was similar between WT and Jmjd3 cKO mice (9.7% vs. 11.3%) (Fig. 1e). These results suggest that Jmjd3 ablation markedly promotes Th17 and Th2 cell differentiation in the small intestine and colon and decreases Th1 cell differentiation in the small intestine and spleen. However, its effects on lymphatic Th1, Th2, Th17, and Treg cells are relatively small.


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 deletion alters CD4+ T cell populations in different organsFrequency of CD4+ T cell populations isolated from (a) small intestine, (b) spleen, (c) LN, and (d) colon of WT and Jmjd3 cKO mice (e) Frequency of thymic and splenic nTreg cell populations (CD25+CD4+GFP+) from WT and Jmjd3 cKO Foxp3-GFP reporter mice. Mean percentage of the indicated T cell populations ± SD shown as histograms (right panel)(representative of three independent experiments, n = 3 for each group, *p < 0.05 determined by Student's t-test).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4274750&req=5

Figure 1: Jmjd3 deletion alters CD4+ T cell populations in different organsFrequency of CD4+ T cell populations isolated from (a) small intestine, (b) spleen, (c) LN, and (d) colon of WT and Jmjd3 cKO mice (e) Frequency of thymic and splenic nTreg cell populations (CD25+CD4+GFP+) from WT and Jmjd3 cKO Foxp3-GFP reporter mice. Mean percentage of the indicated T cell populations ± SD shown as histograms (right panel)(representative of three independent experiments, n = 3 for each group, *p < 0.05 determined by Student's t-test).
Mentions: Recent studies have shown that Jmjd3 interacts with T-bet, a master transcription factor in Th1 cell differentiation, in a histone demethylase activity-independent manner39,40. However, the in vivo function of Jmjd3 in T cell differentiation remains unknown. To address this, we used fluorescence-activated cell sorting (FACS) analysis to determine the percentages of CD4+ T cell subsets in lymphocytes isolated from small intestine, spleen, lymph node (LN), and colon of wild-type (WT) and Jmjd3 cKO mice. Compared with WT mice, IFN-γ-producing Th1 cells were slightly increased in the LN and colon in Jmjd3 cKO mice, but decreased in the small intestine and spleen. IL-4-producing Th2 cells were increased in the small intestine and colon, but not significantly changed in spleen or LN (Fig. 1a-d). The percentage of IL-17-producing Th17 cells was substantially higher in the small intestines of Jmjd3 cKO mice compared with WT mice (14.8% vs. 3.8%) and in the colons (17.5% vs. 5.2%) of Jmjd3 cKO mice compared with WT mice (Fig. 1a,d). We did not observe any appreciable changes in lymphatic Th17 cells between WT and Jmjd3 cKO mice (Fig. 1c). Foxp3-expressing Treg cells were slightly higher in the small intestine, spleen, and LN (Fig. 1a-c), but not in the colon of Jmjd3 cKO mice compared with WT mice. To determine the effects of Jmjd3 on thymic and splenic natural Treg (nTreg) cell populations, WT and Jmjd3 cKO Foxp3-GFP reporter mice were generated. FACS analysis revealed that the percentage of thymic GFP+ nTreg cells was approximately 50% lower in Jmjd3 cKO mice than in WT mice. In contrast, the splenic nTreg cell population percentage was similar between WT and Jmjd3 cKO mice (9.7% vs. 11.3%) (Fig. 1e). These results suggest that Jmjd3 ablation markedly promotes Th17 and Th2 cell differentiation in the small intestine and colon and decreases Th1 cell differentiation in the small intestine and spleen. However, its effects on lymphatic Th1, Th2, Th17, and Treg cells are relatively small.

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