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GC- and AT-rich chromatin domains differ in conformation and histone modification status and are differentially modulated by Rpd3p.

Dekker J - Genome Biol. (2007)

Bottom Line: We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription.Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC-rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin.We propose that GC-rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.

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Affiliation: Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Plantation Street, Worcester, MA 01605-4321, USA. job.dekker@umassmed.edu

ABSTRACT

Background: Base-composition varies throughout the genome and is related to organization of chromosomes in distinct domains (isochores). Isochore domains differ in gene expression levels, replication timing, levels of meiotic recombination and chromatin structure. The molecular basis for these differences is poorly understood.

Results: We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription. Using 3C analysis we show that, along chromosome III, GC-rich isochores have a chromatin structure that is characterized by lower chromatin interaction frequencies compared to AT-rich isochores, which may point to a more extended chromatin conformation. In addition, we find that throughout the genome, GC-rich and AT-rich genes display distinct levels of histone modifications. Interestingly, elimination of the histone deacetylase Rpd3p differentially affects conformation of GC- and AT-rich domains. Further, deletion of RPD3 activates expression of GC-rich genes more strongly than AT-rich genes. Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC-rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin.

Conclusion: We find that GC-rich and AT-rich chromatin domains display distinct chromatin conformations and are marked by distinct patterns of histone modifications. We identified the histone deacetylase Rpd3p as an attenuator of these base composition-dependent differences in chromatin status. We propose that GC-rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.

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Rpd3p displays base composition-dependent activity. (a) Patterns of base composition (line) and gene activation (gray area) in rpd3Δ cells along chromosome III as determined by sliding window analysis using a window size of 30 kb and the transcription start sites as midpoints (step size 1 open reading frame). The genome-wide dataset describing the effect of deletion of RPD3 was produced by Fazzio et al. [37]. (b) Genes were grouped in six groups dependent on the average base composition of the 4 kb region centered on the start site of the gene. For each group the average Log of the fold change in transcription in an rpd3Δ mutant compared to wild type was calculated. More GC-rich genes are more activated than more AT-rich genes (P < 10-13 for the difference between the most GC-rich genes and the most AT-rich genes). (c) The moving average (window size 200, step size 1 open reading frame) of the Log of the fold change in transcript level in rpd3Δ is plotted against transcript level in wild type. (d) A similar analysis as in (c) is performed with genes that are in the most GC-rich group and in the most AT-rich group (window size of 100 genes). GC-rich genes are more up-regulated in rpd3Δ cells.
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Figure 4: Rpd3p displays base composition-dependent activity. (a) Patterns of base composition (line) and gene activation (gray area) in rpd3Δ cells along chromosome III as determined by sliding window analysis using a window size of 30 kb and the transcription start sites as midpoints (step size 1 open reading frame). The genome-wide dataset describing the effect of deletion of RPD3 was produced by Fazzio et al. [37]. (b) Genes were grouped in six groups dependent on the average base composition of the 4 kb region centered on the start site of the gene. For each group the average Log of the fold change in transcription in an rpd3Δ mutant compared to wild type was calculated. More GC-rich genes are more activated than more AT-rich genes (P < 10-13 for the difference between the most GC-rich genes and the most AT-rich genes). (c) The moving average (window size 200, step size 1 open reading frame) of the Log of the fold change in transcript level in rpd3Δ is plotted against transcript level in wild type. (d) A similar analysis as in (c) is performed with genes that are in the most GC-rich group and in the most AT-rich group (window size of 100 genes). GC-rich genes are more up-regulated in rpd3Δ cells.

Mentions: First, we examined whether the genes in the relatively large 90 kb GC-rich and AT-rich isochores along chromosome III are differentially affected by deletion of RPD3. We calculated the average change in transcription in rpd3Δ versus wild-type cells along chromosome III as a function of gene position along the chromosome. Comparison of average base composition with average global change in transcription shows that deletion of RPD3 had little effect on transcription of the central AT-rich isochore domain. In contrast, transcription in the GC-rich isochore domains was significantly more increased (Figure 4a; P < 0.001).


GC- and AT-rich chromatin domains differ in conformation and histone modification status and are differentially modulated by Rpd3p.

Dekker J - Genome Biol. (2007)

Rpd3p displays base composition-dependent activity. (a) Patterns of base composition (line) and gene activation (gray area) in rpd3Δ cells along chromosome III as determined by sliding window analysis using a window size of 30 kb and the transcription start sites as midpoints (step size 1 open reading frame). The genome-wide dataset describing the effect of deletion of RPD3 was produced by Fazzio et al. [37]. (b) Genes were grouped in six groups dependent on the average base composition of the 4 kb region centered on the start site of the gene. For each group the average Log of the fold change in transcription in an rpd3Δ mutant compared to wild type was calculated. More GC-rich genes are more activated than more AT-rich genes (P < 10-13 for the difference between the most GC-rich genes and the most AT-rich genes). (c) The moving average (window size 200, step size 1 open reading frame) of the Log of the fold change in transcript level in rpd3Δ is plotted against transcript level in wild type. (d) A similar analysis as in (c) is performed with genes that are in the most GC-rich group and in the most AT-rich group (window size of 100 genes). GC-rich genes are more up-regulated in rpd3Δ cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2394764&req=5

Figure 4: Rpd3p displays base composition-dependent activity. (a) Patterns of base composition (line) and gene activation (gray area) in rpd3Δ cells along chromosome III as determined by sliding window analysis using a window size of 30 kb and the transcription start sites as midpoints (step size 1 open reading frame). The genome-wide dataset describing the effect of deletion of RPD3 was produced by Fazzio et al. [37]. (b) Genes were grouped in six groups dependent on the average base composition of the 4 kb region centered on the start site of the gene. For each group the average Log of the fold change in transcription in an rpd3Δ mutant compared to wild type was calculated. More GC-rich genes are more activated than more AT-rich genes (P < 10-13 for the difference between the most GC-rich genes and the most AT-rich genes). (c) The moving average (window size 200, step size 1 open reading frame) of the Log of the fold change in transcript level in rpd3Δ is plotted against transcript level in wild type. (d) A similar analysis as in (c) is performed with genes that are in the most GC-rich group and in the most AT-rich group (window size of 100 genes). GC-rich genes are more up-regulated in rpd3Δ cells.
Mentions: First, we examined whether the genes in the relatively large 90 kb GC-rich and AT-rich isochores along chromosome III are differentially affected by deletion of RPD3. We calculated the average change in transcription in rpd3Δ versus wild-type cells along chromosome III as a function of gene position along the chromosome. Comparison of average base composition with average global change in transcription shows that deletion of RPD3 had little effect on transcription of the central AT-rich isochore domain. In contrast, transcription in the GC-rich isochore domains was significantly more increased (Figure 4a; P < 0.001).

Bottom Line: We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription.Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC-rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin.We propose that GC-rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Plantation Street, Worcester, MA 01605-4321, USA. job.dekker@umassmed.edu

ABSTRACT

Background: Base-composition varies throughout the genome and is related to organization of chromosomes in distinct domains (isochores). Isochore domains differ in gene expression levels, replication timing, levels of meiotic recombination and chromatin structure. The molecular basis for these differences is poorly understood.

Results: We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription. Using 3C analysis we show that, along chromosome III, GC-rich isochores have a chromatin structure that is characterized by lower chromatin interaction frequencies compared to AT-rich isochores, which may point to a more extended chromatin conformation. In addition, we find that throughout the genome, GC-rich and AT-rich genes display distinct levels of histone modifications. Interestingly, elimination of the histone deacetylase Rpd3p differentially affects conformation of GC- and AT-rich domains. Further, deletion of RPD3 activates expression of GC-rich genes more strongly than AT-rich genes. Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC-rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin.

Conclusion: We find that GC-rich and AT-rich chromatin domains display distinct chromatin conformations and are marked by distinct patterns of histone modifications. We identified the histone deacetylase Rpd3p as an attenuator of these base composition-dependent differences in chromatin status. We propose that GC-rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.

Show MeSH