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Transcriptional Enhancers in the Regulation of T Cell Differentiation.

Nguyen ML, Jones SA, Prier JE, Russ BE - Front Immunol (2015)

Bottom Line: The changes in phenotype and function that characterize the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression.Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs).We discuss the central role of TEs in regulating T cell differentiation, both in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne , Melbourne, VIC , Australia.

ABSTRACT
The changes in phenotype and function that characterize the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression. In turn, these changes are choreographed by the interplay between transcription factors and epigenetic regulators that act to restructure the genome, ultimately ensuring lineage-appropriate gene expression. Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs). We discuss the central role of TEs in regulating T cell differentiation, both in health and disease.

No MeSH data available.


Differentiation-dependent chromatin looping of the type 2 and interferon gamma loci. (A) In naïve CD4+ T cells, the promoters of the genes encoding IL-4, IL-5, and IL-13 are clustered together. Following Th2 differentiation, the locus control region (LCR) contained within a 3′ intron of the Rad50 gene loops onto the clustered promoters, licensing cytokine expression. DNAse1 hypersensitive sites are shown by arrows, with sites shown to be critical for cytokine expression named. (B) In contrast to the type 2 locus, chromatin loops at the murine interferon-gamma (IFNG) locus are acquired as naïve CD4+ T cells differentiate to the Th1 fate. Enhancers are shown by purple circles with their coordinates shown relative to the transcription start site (0 kb).
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Figure 4: Differentiation-dependent chromatin looping of the type 2 and interferon gamma loci. (A) In naïve CD4+ T cells, the promoters of the genes encoding IL-4, IL-5, and IL-13 are clustered together. Following Th2 differentiation, the locus control region (LCR) contained within a 3′ intron of the Rad50 gene loops onto the clustered promoters, licensing cytokine expression. DNAse1 hypersensitive sites are shown by arrows, with sites shown to be critical for cytokine expression named. (B) In contrast to the type 2 locus, chromatin loops at the murine interferon-gamma (IFNG) locus are acquired as naïve CD4+ T cells differentiate to the Th1 fate. Enhancers are shown by purple circles with their coordinates shown relative to the transcription start site (0 kb).

Mentions: IL-4 is encoded within the type 2 locus that also encodes the Th2 cytokines IL-5 and IL-13 (Figure 4A). Expression of these three genes is co-regulated via a mechanism that involves chromatin looping such that the three gene promoters are in physical interaction (53–56). Interestingly, this interaction is preconfigured in naïve CD4+ T cells, despite the fact that naïve T cells are not immediately competent for transcription of the type 2 gene cluster. Indeed, this arrangement is also present in B cells and fibroblasts, both of which are capable of expressing IL-4 and IL-13, and thus the looping mechanisms that regulate transcription of the type 2 cluster in CD4+ T cells are not cell type-specific. Within T cells, the preconfigured state of the type 2 locus is critically dependent on the STAT6 TF, since in Stat6−/− cells, chromatin looping is dramatically reduced (55). The reason for this dependence appears to be that STAT6 directly binds throughout the type 2 locus, and therefore may be involved in mediating looping interactions. Moreover, STAT6 is also required for up-regulation of GATA3, which is itself required for type 2 locus expression (53).


Transcriptional Enhancers in the Regulation of T Cell Differentiation.

Nguyen ML, Jones SA, Prier JE, Russ BE - Front Immunol (2015)

Differentiation-dependent chromatin looping of the type 2 and interferon gamma loci. (A) In naïve CD4+ T cells, the promoters of the genes encoding IL-4, IL-5, and IL-13 are clustered together. Following Th2 differentiation, the locus control region (LCR) contained within a 3′ intron of the Rad50 gene loops onto the clustered promoters, licensing cytokine expression. DNAse1 hypersensitive sites are shown by arrows, with sites shown to be critical for cytokine expression named. (B) In contrast to the type 2 locus, chromatin loops at the murine interferon-gamma (IFNG) locus are acquired as naïve CD4+ T cells differentiate to the Th1 fate. Enhancers are shown by purple circles with their coordinates shown relative to the transcription start site (0 kb).
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Related In: Results  -  Collection

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Figure 4: Differentiation-dependent chromatin looping of the type 2 and interferon gamma loci. (A) In naïve CD4+ T cells, the promoters of the genes encoding IL-4, IL-5, and IL-13 are clustered together. Following Th2 differentiation, the locus control region (LCR) contained within a 3′ intron of the Rad50 gene loops onto the clustered promoters, licensing cytokine expression. DNAse1 hypersensitive sites are shown by arrows, with sites shown to be critical for cytokine expression named. (B) In contrast to the type 2 locus, chromatin loops at the murine interferon-gamma (IFNG) locus are acquired as naïve CD4+ T cells differentiate to the Th1 fate. Enhancers are shown by purple circles with their coordinates shown relative to the transcription start site (0 kb).
Mentions: IL-4 is encoded within the type 2 locus that also encodes the Th2 cytokines IL-5 and IL-13 (Figure 4A). Expression of these three genes is co-regulated via a mechanism that involves chromatin looping such that the three gene promoters are in physical interaction (53–56). Interestingly, this interaction is preconfigured in naïve CD4+ T cells, despite the fact that naïve T cells are not immediately competent for transcription of the type 2 gene cluster. Indeed, this arrangement is also present in B cells and fibroblasts, both of which are capable of expressing IL-4 and IL-13, and thus the looping mechanisms that regulate transcription of the type 2 cluster in CD4+ T cells are not cell type-specific. Within T cells, the preconfigured state of the type 2 locus is critically dependent on the STAT6 TF, since in Stat6−/− cells, chromatin looping is dramatically reduced (55). The reason for this dependence appears to be that STAT6 directly binds throughout the type 2 locus, and therefore may be involved in mediating looping interactions. Moreover, STAT6 is also required for up-regulation of GATA3, which is itself required for type 2 locus expression (53).

Bottom Line: The changes in phenotype and function that characterize the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression.Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs).We discuss the central role of TEs in regulating T cell differentiation, both in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne , Melbourne, VIC , Australia.

ABSTRACT
The changes in phenotype and function that characterize the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression. In turn, these changes are choreographed by the interplay between transcription factors and epigenetic regulators that act to restructure the genome, ultimately ensuring lineage-appropriate gene expression. Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs). We discuss the central role of TEs in regulating T cell differentiation, both in health and disease.

No MeSH data available.