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Review
. 2009:78:245-71.
doi: 10.1146/annurev.biochem.78.071107.134639.

Genome-wide views of chromatin structure

Oliver J Rando  1 , Howard Y Chang
Affiliations
Review

Genome-wide views of chromatin structure

Oliver J Rando et al. Annu Rev Biochem. 2009.

Abstract

Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin, which affects most processes that occur on DNA. Along with genetic and biochemical studies of resident chromatin proteins and their modifying enzymes, mapping of chromatin structure in vivo is one of the main pillars in our understanding of how chromatin relates to cellular processes. In this review, we discuss the use of genomic technologies to characterize chromatin structure in vivo, with a focus on data from budding yeast and humans. The picture emerging from these studies is the detailed chromatin structure of a typical gene, where the typical behavior gives insight into the mechanisms and deep rules that establish chromatin structure. Important deviation from the archetype is also observed, usually as a consequence of unique regulatory mechanisms at special genomic loci. Chromatin structure shows substantial conservation from yeast to humans, but mammalian chromatin has additional layers of complexity that likely relate to the requirements of multicellularity such as the need to establish faithful gene regulatory mechanisms for cell differentiation.

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Figures

Figure 1
Figure 1
Chromatin map of typical active genes in yeast and human. (a) Schematic of a typical yeast gene, showing distributions of various histone marks associated with transcription (H3K4 methylation, H3K36 methylation, most acetylation), and associated with histone replacement (H4K16ac, H3K56ac). Boxes indicate prominent sequence rules underlying nucleosome positioning at a typical gene—antinucleosomal poly-dA/dT tracts (red box) are found at many promoters and may specify the abundant nucleosome-free regions, while pronucleosomal sequences (green box) are often found associated with the +1 nucleosome. (b) Schematic of an average gene, enhancer, and insulator in human cells. H3K4me3 is found near the TSS, while H3K4me2, H3K9me1, H2BK5me1, H3K27me1, and H4K20me1 are distributed over the TSS and into the gene body. The me1 occupancy patterns of H3K9 and H3K27 are in striking contrast to the repressive me3 patterns of occupancy, illustrating that the methylation status of a single residue may signal distinct outcomes (94). However, to date no protein has been identified that that specifically recognizes H3K9me1 or H3K27me1. H3K36me3, H3R2me2a, and H4K12ac are distributed over the body of genes. Several histone acetylations, including H2AK9ac, H2BK5ac, H3K9ac, H3K18ac, H3K27ac, H3K36ac, and H4K91ac, are mainly associated with regions around the TSS of active genes, whereas a number of other histone acetylations also extend into the bodies of active genes. While gene-proximal promoters are occupied by H3K4me3, enhancers typically show H3K4me1 and are also occupied by the histone acetyltransferase p300 (90). In a separate study, intergenic DHSs (a subset of which likely includes enhancers) were found to be associated with H2A.Z, H3K4me1, H3K4me2, H3K4me3, H3K9me1, H3K18ac, and H2BK5ac (95). Some of these differences (e.g., H3K4 methylation states) from the two studies suggest that there may be multiple and cell type–specific chromatin signatures of enhancers. Finally, insulators are associated with CTCF binding, strongly phased and positioned nucleosomes that contain H2A.Z, and modifications such as H3K4me3, H3K4me2, H3K9me1, along with other marks typically associated with active TSS.
Figure 2
Figure 2
Chromatin map of the human HOXA locus. The HOX loci are prominent examples of H3K4me3/H3K27me3 bivalent domains in ESCs that resolve upon differentiation. This chromatin map of ~100 kb of HOXA from differentiated lung fibroblasts shows that activated HOX genes and their surrounding ncRNAs and intergenic regions are broadly occupied by H3K4me3/2; the silent HOX genes are broadly occupied by H3K27me3. The resolution of bivalent domains implies that the histone methylation in ESCs must be erased upon differentiation, enzymatically or via histone turnover. Of course, even enzymatic erasure could occur via general (global erasure of all of some mark at a given developmental stage) or specific schemes. The H3K27me3 demethylase UTX does not occupy the HOX in undifferentiated ESCs. Upon differentiation, UTX is focally targeted to the first ~500 bases of multiple HOX genes concomitant with loss of occupancy of PcG proteins and H3K27me3 (106, 153, 154), but this can occur in the midst of broad H3K27me3 domains or H3K4me3/2 domains (106). Reprinted with permission from Reference .
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