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Review
. 2012 Nov;40(21):10719-41.
doi: 10.1093/nar/gks865. Epub 2012 Sep 21.

Histone H2A variants in nucleosomes and chromatin: more or less stable?

Clemens Bönisch  1 , Sandra B Hake
Affiliations
Review

Histone H2A variants in nucleosomes and chromatin: more or less stable?

Clemens Bönisch et al. Nucleic Acids Res. 2012 Nov.

Abstract

In eukaryotes, DNA is organized together with histones and non-histone proteins into a highly complex nucleoprotein structure called chromatin, with the nucleosome as its monomeric subunit. Various interconnected mechanisms regulate DNA accessibility, including replacement of canonical histones with specialized histone variants. Histone variant incorporation can lead to profound chromatin structure alterations thereby influencing a multitude of biological processes ranging from transcriptional regulation to genome stability. Among core histones, the H2A family exhibits highest sequence divergence, resulting in the largest number of variants known. Strikingly, H2A variants differ mostly in their C-terminus, including the docking domain, strategically placed at the DNA entry/exit site and implicated in interactions with the (H3-H4)(2)-tetramer within the nucleosome and in the L1 loop, the interaction interface of H2A-H2B dimers. Moreover, the acidic patch, important for internucleosomal contacts and higher-order chromatin structure, is altered between different H2A variants. Consequently, H2A variant incorporation has the potential to strongly regulate DNA organization on several levels resulting in meaningful biological output. Here, we review experimental evidence pinpointing towards outstanding roles of these highly variable regions of H2A family members, docking domain, L1 loop and acidic patch, and close by discussing their influence on nucleosome and higher-order chromatin structure and stability.

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Figures

Figure 1.
Figure 1.
The crystal structure of the nucleosome. (A) Amino acid sequence of histone H2A type 1 from Xenopus leavis (NCBI reference sequence: NP_001089684.1). α-helices are indicated below and important structural features are highlighted with coloured boxes (L1 loop: magenta, acidic patch: cyan, docking domain: orange). The colour code for the amino acids is as follows: red: small, hydrophobic (A, V, F, P, M, I, L, W); blue: acidic (D, E); magenta: basic (R, K); green: hydroxyl, sulphydryl, amine, glycine (S, T, Y, H, C, N, G, Q). (B) Nucleosome crystal structure based on [(8), PDB ID: 1AOI]. H2A is shown in yellow, H2B in red, H3 in blue, H4 in green and DNA in light grey. L1 loop, acidic patch and docking domain are highlighted and shown in magenta, cyan and orange, respectively. Zoomed images of docking domain and L1–L1 interface are depicted on the right. All pictures were generated using PyMOL (14).
Figure 2.
Figure 2.
Amino acid sequences of human H2A variants. Alignments of human H2A type 1 (NCBI reference sequence: NP_003501.1) with human (A) H2A.X (NP_002096.1), (B) H2A.Z.1 (NP_002097.1), (C) H2A.Bbd (NP_001017990.1) and (D) macroH2A.1.2 (NP_004884.1). Important structural features are highlighted with coloured boxes. For details on colour coding see legend of Figure 1. H2A and H2A.X amino acids that are discussed in the text are highlighted according to the figure key. The consensus symbols below the alignment are as follows: an asterisk to indicate fully conserved residues, a colon to indicate conservation between groups of strongly similar properties and a period to indicate conservation between groups of weakly similar properties. (D) MacroH2A.1.2's linker region (amino acids 122–160) and macro domain (amino acids 161–370) are highlighted with dark grey and light grey boxes, respectively. All alignments were carried out using the ClustalW alignment tool on the EMBL-EBI homepage (28,29).
Figure 3.
Figure 3.
Amino acid sequences of human H2A.Z variants. Alignment of human H2A.Z.1 with H2A.Z.2.1 and H2A.Z.2.2. α-helices are indicated below and structural features that are discussed in the text are highlighted with coloured boxes. H2A.Z amino acids that are discussed in the text are highlighted according to the figure key. For details on colour coding and consensus symbols see legends of Figures 1 and 2, respectively. Sequence elements required for H2A.Z function (75) are indicated by grey boxes below and sites of PTMs as described in the figure key. Alignment was carried out using the ClustalW alignment tool on the EMBL-EBI homepage (28,29).
Figure 4.
Figure 4.
The acidic patch regulates chromatin structure by interaction with the H4 tail. The H4 tail can engage in intrafibre interactions with the acidic patch of neighbouring nucleosomes within the same chromatin fibre to form more compact secondary structures (left). Alternatively, it can form different interfibre interactions with DNA and histones of other chromatin fibres to form large tertiary oligomeric complexes (right). Which interactions are preferred is influenced by acidic patch alterations in H2A variants. The extended acidic patch of H2A.Z fosters compact secondary structure formation (right), whereas the reduced acidic patch of H2A.Bbd leads to preferred oligomerization (left). DNA is shown in black, H2A in yellow, H2B in red, H3 in blue and H4 in green. Flexible histone tails for histones other than H4 are omitted for clarity.
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