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. 2011 Jun;21(6):875-84.
doi: 10.1101/gr.117465.110. Epub 2011 Apr 22.

Stable and dynamic nucleosome states during a meiotic developmental process

Liye Zhang  1 , Hong Ma, B Franklin Pugh
Affiliations

Stable and dynamic nucleosome states during a meiotic developmental process

Liye Zhang et al. Genome Res. 2011 Jun.

Abstract

The plasticity of chromatin organization as chromosomes undergo a full compendium of transactions including DNA replication, recombination, chromatin compaction, and changes in transcription during a developmental program is unknown. We generated genome-wide maps of individual nucleosome organizational states, including positions and occupancy of all nucleosomes, and H3K9 acetylation and H3K4, K36, K79 tri-methylation, during meiotic spore development (gametogenesis) in Saccharomyces. Nucleosome organization was remarkably constant as the genome underwent compaction. However, during an acute meiotic starvation response, nucleosomes were repositioned to alter the accessibility of select transcriptional start sites. Surprisingly, the majority of the meiotic programs did not use this nucleosome repositioning, but was dominated by antisense control. Histone modification states were also remarkably stable, being abundant at specific nucleosome positions at three-quarters of all genes, despite most genes being rarely transcribed. Our findings suggest that, during meiosis, the basic features of genomic chromatin organization are essentially a fixed property of chromosomes, but tweaked in a restricted and program-specific manner.

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Figures

Figure 1.
Figure 1.
Nucleosome organization around genes throughout sporulation. (A) Composite nucleosome distribution traces for six time points in the meiosis/sporulation program are color-coded as indicated. Nucleosome midpoint density is represented by sequencing tag counts from cross-linked, MNase-digested, H3 immunoprecipitated, and gel-purified samples. Distributions were normalized such that the total tag count in each sample was equal. Tag counts are distributed about 6576 transcript start (TSS) and end (TES) sites in 3-bp bins and 15-bp bins, respectively, and smoothed via a three-bin moving average. The percentage of regions analyzed is indicated by the black trace and covers a minimum of ±300 bp from the TSS or TES and a maximum of 300 bp from the next TSS or TES. Bin counts were normalized to the number of regions represented in each bin. (B) Nucleosome fuzziness was taken to be the standard deviation of tag locations for each nucleosome. The average fuzziness per bin was determined, then plotted as described in A. (Right) A frequency distribution of nucleosome fuzziness at various meiotic time points. Color codes are as in A, except that YPD is represented by a black trace. (C) Frequency distribution of nucleosomal widths (distance between the W/+ and C/− MNase-digested borders).
Figure 2.
Figure 2.
Nucleosome organization around genomic features throughout sporulation. (A–F) Nucleosomal midpoint tags were distributed around the indicated number of genomic features as described in Figure 1, except that bins were 15 bp. Percentages of regions analyzed are on the right.
Figure 3.
Figure 3.
+1 nucleosome shift is linked with carbon starvation regulation. (A) +1 nucleosome midpoint distances from the position found in YPD were calculated for each gene (rows) at all time points (columns) and displayed as a cluster plot. Three distinct groups were identified by k-means clustering. Distances shifted downstream in a positive direction are color-coded yellow. Upstream shifts are colored blue. Equivalent shifts were evident across the genic nucleosomal arrays. (B) Venn diagram and χ-test are shown for the overlap of the indicated cluster of genes and those genes most up- or down-regulated (as indicated) upon carbon starvation (Bradley et al. 2009). Composite nucleosome distributions around the TSS are shown for the set of intersecting genes.
Figure 4.
Figure 4.
Nucleosomal and histone modification distribution around genomic features. (A) Distributions of indicated H3 modification states (rows of panels) are plotted around the TSS and TES for all genes. Traces reflecting different time points in the sporulation program are color-coded as indicated, and further described in Figure 1A. Total tag counts in each sample were scaled to reflect the bulk distribution, measured by immunoblotting (Supplemental Fig. S8). Consequently, the plots reflect the level of modified nucleosomes, not the density of modification per H3 nucleosome. The H3K79me3 antibody may have significant cross-reactivity with me2. Cluster plots for H3K4me3 (B) and H3K36me3 (D) changes on a gene-by-gene basis show that both H3K4me3 and H3K36me3 are linked with transcription. In contrast to A, the total tag count for all samples (H3, H3K4me3, and H3K36me3) were normalized to be equal. Each row included gene-centered log2 transformed H3K4me3/H3 ratios (from the 0- to 500-bp region relative to TSS for H3K4me3 and the 300- to 1000-bp region relative to TSS for H3K36me3) for all six time points. Gene-centering means that the average of each row is set to zero. All genes were arranged by k-means clustering (k = 5). The number of genes in each cluster is indicated. One cluster was omitted as it displayed no changes. Corresponding changes in mRNA levels (Primig et al. 2000; Williams et al. 2002) are shown. Levels of mRNA were gene centered and log2 transformed. (C) χ-tests between clusters of H3K4me3 and H3K36me3 suggest that two methylation marks are significantly coincident. Venn diagram relating the overlap of clusters 1–4 in B with the corresponding clusters in D. Values below the Venn diagram reflect log10 P-values (χ-test) of the overlapping membership.
Figure 5.
Figure 5.
Distribution of nucleosomes and histone modification states around meiotic recombination hot and cold spots. The distribution of nucleosomal tags and levels of the indicated modification states around double-strand break (DSB) hotspots and cold spots (Borde et al. 2009) during the sporulation program are displayed in the first two columns of graphs. To assess nucleosome densities, plots should be compared against Figure 2A. The third column displays tag distributions around the TSS as shown in Supplemental Figure S9B for comparison, but is highly smoothed to achieve the lower resolution of the DSB sites.
Figure 6.
Figure 6.
H3K4me3 provides a signature of repressive antisense transcription. The ratio of H3K4me3 density at the 5′ end to the 3′ end of every gene was calculated. The intersecting genes of meiotic specific genes and the genes having log2 ratios that were negative at rich media were selected and k-means (k = 3) clustered (n = 124). The cluster plot is shown on the left and is turned 90° from the normal orientation. Genes are columns, rows are time points, and blue/black/yellow color scale reflects the log2 5′/3′ ratio. The top Venn diagram shows the overlap between these genes and those that produce greater antisense than sense transcription (Parkhomchuk et al. 2009). The bottom Venn diagram shows the overlap with sporulation-induced genes (Chu et al. 1998). χ-test P-values are shown.
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