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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.


Characteristics of active, poised, and repressed transcriptional enhancers and their cognate gene promoters. Active transcriptional enhancers are bordered by widely spaced nucleosomes, baring modifications including H3K4me2 and H3K27Ac, and are bound by the histone acetyltransferase p300 and lineage-specific transcription factors. Active enhancers give rise to eRNAs, and are associated with promoters baring H3K27Ac and H3K4me3. Relative to active enhancers, poised enhancers do not give rise to eRNAs, have H3K27me3 in place of H3K27Ac, and have reduced chromatin accessibility. Poised enhancers are also bound by the Polycomb Repressive Complex 2 (PRC2), and their associated enhancers often have a bivalent signature. Finally, repressed enhancers are characterized by dense nucleosome assemblages baring H3K27me3, and are bound by PRC2.
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Figure 2: Characteristics of active, poised, and repressed transcriptional enhancers and their cognate gene promoters. Active transcriptional enhancers are bordered by widely spaced nucleosomes, baring modifications including H3K4me2 and H3K27Ac, and are bound by the histone acetyltransferase p300 and lineage-specific transcription factors. Active enhancers give rise to eRNAs, and are associated with promoters baring H3K27Ac and H3K4me3. Relative to active enhancers, poised enhancers do not give rise to eRNAs, have H3K27me3 in place of H3K27Ac, and have reduced chromatin accessibility. Poised enhancers are also bound by the Polycomb Repressive Complex 2 (PRC2), and their associated enhancers often have a bivalent signature. Finally, repressed enhancers are characterized by dense nucleosome assemblages baring H3K27me3, and are bound by PRC2.

Mentions: With the recent advent of tools, such as ChIP-Seq, which have allowed the genome-wide distribution of proteins that interact with the genome to be studied, the classic definition of TEs has been further refined to show that, in vivo, TEs exist in poised, active, and repressed states, with each state characterized by unique histone PTM profiles, and unique TF and transcriptional co-regulator-binding profiles [reviewed in Ref. (38); Figure 2]. For instance, TEs of active genes are characterized by deposition of the activating H3K4me2 and H3K27Ac PTMs, while being depleted of the repressive H3K27me3 modification, and having low nucleosome density. On the other hand, repressed enhancers are enriched for H3K27me3, and depleted of activating modifications, and are nucleosome dense (14, 39). Poised enhancers represent a state between activation and repression, being defined by H3K4me1 and H3K27me3 deposition, increased chromatin accessibility relative to repressed enhancers, and binding by the p300 histone acetyltransferase, which also identifies active enhancers. However, unlike active enhancers, poised enhancers lack acetylated histones (40–42). Enhancers marked by this poised signature are not transcribed, but can be rapidly activated following differentiation, and as such, are reminiscent of bivalent domains (H3K4me3+ H3K27me3+) at gene promoters (6, 43). Moreover, like the genes marked by bivalent promoters, poised enhancers appear to regulate genes that enable cell fate specification (42). Thus, poised enhancers may represent “differentiation switches”, whereby their activation drives lineage commitment, while their repression blocks fates associated with the particular genes that they regulate. Finally, as with active enhancers, poised enhancers are bound by lineage defining TFs, which appear to be required to establish the cell state-specific “enhancersomes” [(44) described further below].


Transcriptional Enhancers in the Regulation of T Cell Differentiation.

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

Characteristics of active, poised, and repressed transcriptional enhancers and their cognate gene promoters. Active transcriptional enhancers are bordered by widely spaced nucleosomes, baring modifications including H3K4me2 and H3K27Ac, and are bound by the histone acetyltransferase p300 and lineage-specific transcription factors. Active enhancers give rise to eRNAs, and are associated with promoters baring H3K27Ac and H3K4me3. Relative to active enhancers, poised enhancers do not give rise to eRNAs, have H3K27me3 in place of H3K27Ac, and have reduced chromatin accessibility. Poised enhancers are also bound by the Polycomb Repressive Complex 2 (PRC2), and their associated enhancers often have a bivalent signature. Finally, repressed enhancers are characterized by dense nucleosome assemblages baring H3K27me3, and are bound by PRC2.
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Figure 2: Characteristics of active, poised, and repressed transcriptional enhancers and their cognate gene promoters. Active transcriptional enhancers are bordered by widely spaced nucleosomes, baring modifications including H3K4me2 and H3K27Ac, and are bound by the histone acetyltransferase p300 and lineage-specific transcription factors. Active enhancers give rise to eRNAs, and are associated with promoters baring H3K27Ac and H3K4me3. Relative to active enhancers, poised enhancers do not give rise to eRNAs, have H3K27me3 in place of H3K27Ac, and have reduced chromatin accessibility. Poised enhancers are also bound by the Polycomb Repressive Complex 2 (PRC2), and their associated enhancers often have a bivalent signature. Finally, repressed enhancers are characterized by dense nucleosome assemblages baring H3K27me3, and are bound by PRC2.
Mentions: With the recent advent of tools, such as ChIP-Seq, which have allowed the genome-wide distribution of proteins that interact with the genome to be studied, the classic definition of TEs has been further refined to show that, in vivo, TEs exist in poised, active, and repressed states, with each state characterized by unique histone PTM profiles, and unique TF and transcriptional co-regulator-binding profiles [reviewed in Ref. (38); Figure 2]. For instance, TEs of active genes are characterized by deposition of the activating H3K4me2 and H3K27Ac PTMs, while being depleted of the repressive H3K27me3 modification, and having low nucleosome density. On the other hand, repressed enhancers are enriched for H3K27me3, and depleted of activating modifications, and are nucleosome dense (14, 39). Poised enhancers represent a state between activation and repression, being defined by H3K4me1 and H3K27me3 deposition, increased chromatin accessibility relative to repressed enhancers, and binding by the p300 histone acetyltransferase, which also identifies active enhancers. However, unlike active enhancers, poised enhancers lack acetylated histones (40–42). Enhancers marked by this poised signature are not transcribed, but can be rapidly activated following differentiation, and as such, are reminiscent of bivalent domains (H3K4me3+ H3K27me3+) at gene promoters (6, 43). Moreover, like the genes marked by bivalent promoters, poised enhancers appear to regulate genes that enable cell fate specification (42). Thus, poised enhancers may represent “differentiation switches”, whereby their activation drives lineage commitment, while their repression blocks fates associated with the particular genes that they regulate. Finally, as with active enhancers, poised enhancers are bound by lineage defining TFs, which appear to be required to establish the cell state-specific “enhancersomes” [(44) described further below].

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.