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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.


Examples of transcriptional regulation via modulation of histone modifications. (A) Activation of a repressed chromatin state: repressed chromatin is typified by deposition of histone modifications, including H3K27me3 and densely structured chromatin. In this scenario, activation results from demethylation of H3K27, modulated by the histone demthylase KDM6b, followed by acetylation of residues including H3K27 by a histone acetyl transferase (HAT). Finally, acetylated histones serve as substrates for histone remodeling complexes including BAF and pBAF, which reduce chromatin density, exposing the intervening DNA for access by transcription factors and the transcriptional machinery. (B) Repression of an active chromatin state: active chromatin is typified by acetylated histones, unmethylated CpG residues, and high chromatin accessibility. In this scenario, CpG methylation is catalyzed by a DNA Methyltransferase (DNMT). Methylated CpG residues then serve as a substrate for methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs). Following deacetylation, H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2).
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Figure 1: Examples of transcriptional regulation via modulation of histone modifications. (A) Activation of a repressed chromatin state: repressed chromatin is typified by deposition of histone modifications, including H3K27me3 and densely structured chromatin. In this scenario, activation results from demethylation of H3K27, modulated by the histone demthylase KDM6b, followed by acetylation of residues including H3K27 by a histone acetyl transferase (HAT). Finally, acetylated histones serve as substrates for histone remodeling complexes including BAF and pBAF, which reduce chromatin density, exposing the intervening DNA for access by transcription factors and the transcriptional machinery. (B) Repression of an active chromatin state: active chromatin is typified by acetylated histones, unmethylated CpG residues, and high chromatin accessibility. In this scenario, CpG methylation is catalyzed by a DNA Methyltransferase (DNMT). Methylated CpG residues then serve as a substrate for methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs). Following deacetylation, H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2).

Mentions: The location of nucleosomes is regulated by modulated deposition and removal of post-translation modifications (PTMs) to the solvent-exposed N-termini of histones. These modifications can themselves direct the positioning of nucleosomes by altering the affinity of the histones for the DNA, or may serve as substrates for chromatin remodeling complexes that deposit, evict, and reposition nucleosomes. For instance, histone acetylation, which reduces the net positive charge on the nucleosome, and therefore the intimacy of the association between the DNA and the nucleosome, is thought to destabilize dense chromatin structures, making localized regions of the genome more accessible for transcription (15). Further, acetylation of sequential nucleosomes – a characteristic of regulatory regions of actively transcribed genes – results in charge repulsion, exposing the intervening DNA for access by the transcriptional machinery. Acetylated histones can also serve as substrates for the binding of chromatin remodeling complexes, including the ATP-dependent BAF (BRG1- or HRBM-associated factors) and pBAF (polybromo-associated BAF) complexes (16, 17), which rearrange chromatin to increase DNA accessibility [reviewed in Ref. (18); Figure 1A]. In contrast, histone methylation is associated with both active and repressed chromatin states, depending on the precise residue modified, and the extent of modification (19). For example, trimethylation of lysine 27 of histone 3 (H3K27me3), deposited by the Polycomb Repressive Complex 2 [PRC2 (20)] and removed by histone demethylases KDM6b and UTX (21), is associated with repressed gene transcription. Alternatively, H3K4me3, deposited by the Trithorax group proteins and removed by the Jarid1 histone demethylases, is associated with active transcription [reviewed in Ref. (22)]. Furthermore, histone methylation apparently conveys effects on transcription solely through indirect means, acting as a substrate for nucleosome remodeling complexes. As an example, H3K4me3, which is commonly deposited at active gene promoters, serves as a substrate for binding of the chromodomain-containing remodeler CHD1, which appears to establish accessible chromatin structures by nucleosome repositioning (21).


Transcriptional Enhancers in the Regulation of T Cell Differentiation.

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

Examples of transcriptional regulation via modulation of histone modifications. (A) Activation of a repressed chromatin state: repressed chromatin is typified by deposition of histone modifications, including H3K27me3 and densely structured chromatin. In this scenario, activation results from demethylation of H3K27, modulated by the histone demthylase KDM6b, followed by acetylation of residues including H3K27 by a histone acetyl transferase (HAT). Finally, acetylated histones serve as substrates for histone remodeling complexes including BAF and pBAF, which reduce chromatin density, exposing the intervening DNA for access by transcription factors and the transcriptional machinery. (B) Repression of an active chromatin state: active chromatin is typified by acetylated histones, unmethylated CpG residues, and high chromatin accessibility. In this scenario, CpG methylation is catalyzed by a DNA Methyltransferase (DNMT). Methylated CpG residues then serve as a substrate for methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs). Following deacetylation, H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2).
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Related In: Results  -  Collection

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Figure 1: Examples of transcriptional regulation via modulation of histone modifications. (A) Activation of a repressed chromatin state: repressed chromatin is typified by deposition of histone modifications, including H3K27me3 and densely structured chromatin. In this scenario, activation results from demethylation of H3K27, modulated by the histone demthylase KDM6b, followed by acetylation of residues including H3K27 by a histone acetyl transferase (HAT). Finally, acetylated histones serve as substrates for histone remodeling complexes including BAF and pBAF, which reduce chromatin density, exposing the intervening DNA for access by transcription factors and the transcriptional machinery. (B) Repression of an active chromatin state: active chromatin is typified by acetylated histones, unmethylated CpG residues, and high chromatin accessibility. In this scenario, CpG methylation is catalyzed by a DNA Methyltransferase (DNMT). Methylated CpG residues then serve as a substrate for methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs). Following deacetylation, H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2).
Mentions: The location of nucleosomes is regulated by modulated deposition and removal of post-translation modifications (PTMs) to the solvent-exposed N-termini of histones. These modifications can themselves direct the positioning of nucleosomes by altering the affinity of the histones for the DNA, or may serve as substrates for chromatin remodeling complexes that deposit, evict, and reposition nucleosomes. For instance, histone acetylation, which reduces the net positive charge on the nucleosome, and therefore the intimacy of the association between the DNA and the nucleosome, is thought to destabilize dense chromatin structures, making localized regions of the genome more accessible for transcription (15). Further, acetylation of sequential nucleosomes – a characteristic of regulatory regions of actively transcribed genes – results in charge repulsion, exposing the intervening DNA for access by the transcriptional machinery. Acetylated histones can also serve as substrates for the binding of chromatin remodeling complexes, including the ATP-dependent BAF (BRG1- or HRBM-associated factors) and pBAF (polybromo-associated BAF) complexes (16, 17), which rearrange chromatin to increase DNA accessibility [reviewed in Ref. (18); Figure 1A]. In contrast, histone methylation is associated with both active and repressed chromatin states, depending on the precise residue modified, and the extent of modification (19). For example, trimethylation of lysine 27 of histone 3 (H3K27me3), deposited by the Polycomb Repressive Complex 2 [PRC2 (20)] and removed by histone demethylases KDM6b and UTX (21), is associated with repressed gene transcription. Alternatively, H3K4me3, deposited by the Trithorax group proteins and removed by the Jarid1 histone demethylases, is associated with active transcription [reviewed in Ref. (22)]. Furthermore, histone methylation apparently conveys effects on transcription solely through indirect means, acting as a substrate for nucleosome remodeling complexes. As an example, H3K4me3, which is commonly deposited at active gene promoters, serves as a substrate for binding of the chromodomain-containing remodeler CHD1, which appears to establish accessible chromatin structures by nucleosome repositioning (21).

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.