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The great repression: chromatin and cryptic transcription.

Hennig BP, Fischer T - Transcription (2013)

Bottom Line: The eukaryotic chromatin structure is essential in correctly defining transcription units.Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts.Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Biochemistry Center (BZH); Heidelberg University; Heidelberg, Germany.

ABSTRACT
The eukaryotic chromatin structure is essential in correctly defining transcription units. Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts. Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity.

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Figure 1. Model of key mechanisms controlling cryptic transcription. Panels show schematics representing transcription units in WT (A) or mutant cells (B-D). Colored balls represent nucleosomes (Red: “hot” nucleosomes with a high turnover rate; Blue: “cold” nucleosomes with a low turnover rate; Orange: nucleosomes with an elevated turnover rate). Each row of nucleosomes indicates the chromatin structure of a single cell within the cell population (multiple rows). Red stars represent cryptic promoter sequences, which can either be shielded by the nucleosomes (A) or exposed when chromatin structure is impaired, resulting in cryptic transcription initiation (B-D). The empty circles indicate NFRs in the promoter region. Overall, the model demonstrates: Cryptic promoters are shielded in WT cells with proper chromatin structure (A); Cryptic promoters are exposed leading to cryptic transcription in cells with impaired chromatin structure due to altered nucleosome positioning (B), nucleosome depletion (C) or increased nucleosome turnover rate in gene coding regions (D)
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Figure 1: Figure 1. Model of key mechanisms controlling cryptic transcription. Panels show schematics representing transcription units in WT (A) or mutant cells (B-D). Colored balls represent nucleosomes (Red: “hot” nucleosomes with a high turnover rate; Blue: “cold” nucleosomes with a low turnover rate; Orange: nucleosomes with an elevated turnover rate). Each row of nucleosomes indicates the chromatin structure of a single cell within the cell population (multiple rows). Red stars represent cryptic promoter sequences, which can either be shielded by the nucleosomes (A) or exposed when chromatin structure is impaired, resulting in cryptic transcription initiation (B-D). The empty circles indicate NFRs in the promoter region. Overall, the model demonstrates: Cryptic promoters are shielded in WT cells with proper chromatin structure (A); Cryptic promoters are exposed leading to cryptic transcription in cells with impaired chromatin structure due to altered nucleosome positioning (B), nucleosome depletion (C) or increased nucleosome turnover rate in gene coding regions (D)

Mentions: Interestingly, the previously described mutations lead to a nearly identical phenotype in cryptic transcript accumulation, despite the fact that their effect on chromatin organization is remarkably different. Although these chromatin features might be strongly interconnected, our results showed that histone acetylation or H3K36 methylation does not detectably influence nucleosome positioning or occupancy.1 Similarly, impaired nucleosome positioning or occupancy did not significantly change histone acetylation patterns. How do these seemingly very different mechanisms give rise to such a similar aberrant cryptic transcription phenotype? A possible explanation is that all of these mutations lead to the temporary appearance of NFRs in gene coding regions, which can expose cryptic promoter sequences. The presence of a NFR seems to be one of the most conserved and essential features of eukaryotic promoters, and several lines of evidence show that an artificial NFR can act as a minimal promoter.9,36-38 In contrast, gene-coding regions possess a chromatin structure that prevents the occurrence of NFRs (Fig. 1A). Mutations in the Chd1-type chromatin remodeling factors lead to irregular nucleosome positioning in gene coding regions, and therefore to the random appearance of NFR-like regions (Fig. 1B). Genome-wide nucleosome depletion, such as that observed for the FACT complex mutants or mutations in histone chaperones, do not significantly change the positions of the nucleosomes, but they do increase the time that certain nucleosome positions remain in an unoccupied state,39 creating transient NFRs (Fig. 1C). Increased nucleosome turnover, such as that reported in the set2∆ strain, leads to more frequent assembly and disassembly of nucleosomes, thereby temporarily creating NFRs, which could ultimately be responsible for transcription initiation from these DNA regions (Fig. 1D). Increased acetylation in gene coding regions, as observed for HDAC mutants, might also result in elevated nucleosome turnover, probably by weakening histone-DNA interactions and recruiting bromodomain-containing chromatin remodeling complexes, such as the RSC complex. The crosstalk between histone modifications, turnover, histone occupancy, and nucleosome positioning is poorly understood, and further studies are necessary to better understand this highly regulated network.


The great repression: chromatin and cryptic transcription.

Hennig BP, Fischer T - Transcription (2013)

Figure 1. Model of key mechanisms controlling cryptic transcription. Panels show schematics representing transcription units in WT (A) or mutant cells (B-D). Colored balls represent nucleosomes (Red: “hot” nucleosomes with a high turnover rate; Blue: “cold” nucleosomes with a low turnover rate; Orange: nucleosomes with an elevated turnover rate). Each row of nucleosomes indicates the chromatin structure of a single cell within the cell population (multiple rows). Red stars represent cryptic promoter sequences, which can either be shielded by the nucleosomes (A) or exposed when chromatin structure is impaired, resulting in cryptic transcription initiation (B-D). The empty circles indicate NFRs in the promoter region. Overall, the model demonstrates: Cryptic promoters are shielded in WT cells with proper chromatin structure (A); Cryptic promoters are exposed leading to cryptic transcription in cells with impaired chromatin structure due to altered nucleosome positioning (B), nucleosome depletion (C) or increased nucleosome turnover rate in gene coding regions (D)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042591&req=5

Figure 1: Figure 1. Model of key mechanisms controlling cryptic transcription. Panels show schematics representing transcription units in WT (A) or mutant cells (B-D). Colored balls represent nucleosomes (Red: “hot” nucleosomes with a high turnover rate; Blue: “cold” nucleosomes with a low turnover rate; Orange: nucleosomes with an elevated turnover rate). Each row of nucleosomes indicates the chromatin structure of a single cell within the cell population (multiple rows). Red stars represent cryptic promoter sequences, which can either be shielded by the nucleosomes (A) or exposed when chromatin structure is impaired, resulting in cryptic transcription initiation (B-D). The empty circles indicate NFRs in the promoter region. Overall, the model demonstrates: Cryptic promoters are shielded in WT cells with proper chromatin structure (A); Cryptic promoters are exposed leading to cryptic transcription in cells with impaired chromatin structure due to altered nucleosome positioning (B), nucleosome depletion (C) or increased nucleosome turnover rate in gene coding regions (D)
Mentions: Interestingly, the previously described mutations lead to a nearly identical phenotype in cryptic transcript accumulation, despite the fact that their effect on chromatin organization is remarkably different. Although these chromatin features might be strongly interconnected, our results showed that histone acetylation or H3K36 methylation does not detectably influence nucleosome positioning or occupancy.1 Similarly, impaired nucleosome positioning or occupancy did not significantly change histone acetylation patterns. How do these seemingly very different mechanisms give rise to such a similar aberrant cryptic transcription phenotype? A possible explanation is that all of these mutations lead to the temporary appearance of NFRs in gene coding regions, which can expose cryptic promoter sequences. The presence of a NFR seems to be one of the most conserved and essential features of eukaryotic promoters, and several lines of evidence show that an artificial NFR can act as a minimal promoter.9,36-38 In contrast, gene-coding regions possess a chromatin structure that prevents the occurrence of NFRs (Fig. 1A). Mutations in the Chd1-type chromatin remodeling factors lead to irregular nucleosome positioning in gene coding regions, and therefore to the random appearance of NFR-like regions (Fig. 1B). Genome-wide nucleosome depletion, such as that observed for the FACT complex mutants or mutations in histone chaperones, do not significantly change the positions of the nucleosomes, but they do increase the time that certain nucleosome positions remain in an unoccupied state,39 creating transient NFRs (Fig. 1C). Increased nucleosome turnover, such as that reported in the set2∆ strain, leads to more frequent assembly and disassembly of nucleosomes, thereby temporarily creating NFRs, which could ultimately be responsible for transcription initiation from these DNA regions (Fig. 1D). Increased acetylation in gene coding regions, as observed for HDAC mutants, might also result in elevated nucleosome turnover, probably by weakening histone-DNA interactions and recruiting bromodomain-containing chromatin remodeling complexes, such as the RSC complex. The crosstalk between histone modifications, turnover, histone occupancy, and nucleosome positioning is poorly understood, and further studies are necessary to better understand this highly regulated network.

Bottom Line: The eukaryotic chromatin structure is essential in correctly defining transcription units.Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts.Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Biochemistry Center (BZH); Heidelberg University; Heidelberg, Germany.

ABSTRACT
The eukaryotic chromatin structure is essential in correctly defining transcription units. Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts. Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity.

Show MeSH
Related in: MedlinePlus