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Review
. 2006 Apr 25;103(17):6428-35.
doi: 10.1073/pnas.0600803103. Epub 2006 Mar 29.

Histone H3 variants and their potential role in indexing mammalian genomes: the "H3 barcode hypothesis"

Sandra B Hake  1 , C David Allis
Affiliations
Review

Histone H3 variants and their potential role in indexing mammalian genomes: the "H3 barcode hypothesis"

Sandra B Hake et al. Proc Natl Acad Sci U S A. .

Abstract

In the history of science, provocative but, at times, controversial ideas have been put forward to explain basic problems that confront and intrigue the scientific community. These hypotheses, although often not correct in every detail, lead to increased discussion that ultimately guides experimental tests of the principal concepts and produce valuable insights into long-standing questions. Here, we present a hypothesis, the "H3 barcode hypothesis." Hopefully, our ideas will evoke critical discussion and new experimental approaches that bear on general topics, such as nuclear architecture, epigenetic memory, and cell-fate choice. Our hypothesis rests on the central concept that mammalian histone H3 variants (H3.1, H3.2, and H3.3), although remarkably similar in amino acid sequence, exhibit distinct posttranslational "signatures" that create different chromosomal domains or territories, which, in turn, influence epigenetic states during cellular differentiation and development. Although we restrict our comments to H3 variants in mammals, we expect that the more general concepts presented here will apply to other histone variant families in organisms that employ them.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
H3 variants in different organisms. (A) Schematic of evolutionary appearance of histone H3 variants. All organisms express a centromere-specific H3 variant (CENP-A, filled blue circle). In addition to the centromeric H3 variant, the following H3 variants are expressed in these organisms: S. cerevisiae contains only H3.3 (blue gradient circle); S. pombe expresses a hybrid H3 protein that contains amino acids characteristic for H3.3 and H3.2; Arabidopsis thaliana, Xenopus laevis, and Drosophila melanogaster (for example) express H3.3 and H3.2 (blue circle with white dots); mammals such as Mus musculus and H. sapiens express H3.3, H3.2, H3.1 (white circle with blue dots), and a testis-specific H3.1t (white circle with blue stripes) variant of unknown function. H3.3 has been associated with euchromatin and transcriptional activation. H3.2 and H3.1 might localize to heterochromatin and are involved in transcriptional silencing. (B) Alignment of human noncentromeric histone H3 variants. Differences in amino acid sequence among human H3.3, H3.2, H3.1, and H3.1t are shown in white boxes. Cysteine residues are highlighted in red (Cys 96 in dark red and Cys 110 in pink). Identical amino acids are shown in gray. TS, tissue-specific. The region where most amino acid differences between the variants are found is underlined as a potential chaperone recognition domain (see text for details), and the chaperones binding to H3 variants are depicted below.
Fig. 2.
Fig. 2.
Potential usage of H3 variant-specific cysteines 110 and H3.1-specific cysteine 96. (A) H3 cysteine 110 forms a potential intramolecular disulfide bond (light red box) with H3′ cysteine 110 in the same nucleosome (for details, see text). For simplicity, only the H3–H4 tetramer is shown as top view (Left). All mammalian H3 variants contain cysteine 110 and can potentially participate in disulfide bonding. (Right) H3–H4 dimers. (B) H3.1 cysteine 96 potentially forms intermolecular disulfide bonds (dark red box) with H3.1′ cysteines 96 in different nucleosomes, leading to chromatin condensation and heterochromatin generation (for details, see text). (C) H3.1 cysteine 96 is envisioned to potentially form disulfide bonds (dark red box) with cysteine in LBR on the nuclear envelope or with a cysteine in an as yet unknown protein (X?) in the nucleus (for details, see text). We speculate that chromatin containing H3.1 nucleosomes is preferentially located near the nuclear membrane and irreversibly rendered for transcription regardless of PTMs.
Fig. 3.
Fig. 3.
Epigenetic memory and H3 variants: graphic of different models of epigenetic inheritance (for details, see text). Nucleosomes contain two of H3.3 (blue gradient circle), H3.2 (blue circle with white dots) or H3.1 (white circle with blue dots), and H4 (yellow circle). N-terminal tails of H3 variants are posttranslationally modified: H3.3, active PTMs (green flag); H3.2, silencing PTMs (red flag); H3.1, silencing PTMs that differ from those observed on H3.2 (orange flag). Outside of S-phase, H3.3 can be deposited into chromatin in a RI manner [as either H3.3–H4 tetramers (Left) or H3.3-H4 dimers (Right)] to activate gene transcription immediately, as proposed by Henikoff and colleagues (44). The conservative inheritance model proposes that, during replication, H3–H4 tetramers are distributed on daughter strands in a random fashion. (Left) H3 variant-specific chaperones deposit H3–H4 tetramers onto daughter strands to fill in the gaps, distributing H3 variants by potentially sensing adjacent H3 variants on the same daughter strand. (Right) The semiconservative model of replication, as proposed by Tagami et al. (18), is shown. During replication, nucleosomes are separated into two H3–H4 dimers that are distributed equally onto daughter strands. H3 variant-specific chaperones deposit H3.3–H4 dimers (HIRA), H3.1–H4 dimers (CAF-1), and H3.2–H4 dimers (unknown, ?) to histone dimers on the daughter strands forming homogenic nucleosomes.
Fig. 4.
Fig. 4.
The H3 barcode model to index genomic information and ensure epigenetic memory. (A) Theoretical visualization of H3 variants in two chromosomes (1, 2) of A and B cell types show different banding patterns (white with blue dots, H3.1; blue with white dots, H3.2; blue, H3.3). This H3 variant barcode differs from chromosome to chromosome and cell type to cell type. In this model, H3.1 localizes to constitutive heterochromatin, H3.2 to facultative heterochromatin, and H3.3 to euchromatin. (B) Graphical combination of the three biological codes: the genetic code, the H3 barcode, and the histone code. DNA contains genetic information in the form of genes (white boxes) that have to be activated or silenced at appropriate times and noncoding regions, such as centromeres, telomeres, and satellites (dotted line). Actively transcribed genes contain H3.3 (blue gradient circle) in their chromatin, whereas silenced genes have H3.2 (blue circle with white dots) incorporated. A majority of DNA does not contain any meaningful genetic information and also genes, which are constitutively silent. These genomic regions are indexed by the presence of H3.1 (white circles with blue dots) in the chromatin. The next regulatory step to ensure proper gene expression is the regulation of genes with posttranslational histone modifications (green flag, activation PMTs; red and orange flags, different silencing PMTs). We propose that short-term alterations in gene expression is achieved by the employment of specialized PMTs (e.g., acetylation), but long-term establishment (epigenetic memory) of gene expression involves more stable histone modifications as well as the incorporation of the appropriate histone H3 variants.
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