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Histone H3 is one of the five major histone proteins involved in the structural chromatin in eukaryotic cells. h3 has a major globular domain and a long N-terminal tail, related to the nucleosome structure of a "beaded" structure. Histones are highly post-translationally modified, but histone H3 is the most extensively modified of the five histones. The term "histone H3" alone is deliberately ambiguous because it does not distinguish between sequence variants or modification states. Histone H3 is an important protein in the emerging field of epigenetics, and its sequence variation and variable modification states are thought to play a role in the dynamic and long-term regulation of genes.
During the development of multicellular organisms, cells differentiate by changing their gene expression profiles in response to stimuli or environmental cues. The "cellular memory" mechanism enables cells to remember the fate they have chosen across many cell divisions long after these external stimuli have disappeared. Chromatin has long been suspected to play an important role in these mechanisms, but how epigenetic memory, defined by genetic networks that express and silence genes, is faithfully transmitted to daughter cells during each S phase remains unresolved. We agree with the general view that histone variants, especially H3. 1、h3. 2 and H3. 3, contribute not only to gene expression and silencing events, but also to epigenetic maintenance.
In this view, histone PTMs alone do not explain the establishment of epigenetic memory during several cell divisions. We propose that histone H3 variants help to "index" the genome into functionally independent domains (e.g., euchromatin, facultative heterochromatin, and constitutive heterochromatin), which in turn establish and maintain the appearance of each cell type genetic memory. In support, Nakatani and colleagues provide evidence that mammalian histone H3 protein variants h3.1 and h3.3 are incorporated into chromatin by separate molecular chaperones (CAF-1 and hIRA, respectively). Once properly deposited into chromatin, histone H3 variants must be read by mechanisms that are not yet well understood but may involve PTMs.
The h3.1, h3.2, and h3.3 have distinct biological functions based on cell- and tissue-specific expression patterns and differences in PTMs. We agree with the general view that histone variants index selected chromosomal regions by using mechanisms of selective chromatin assembly of the type described above, regardless of which genetic model actually occurs in the cell. Once in place, we envision that variant nucleosomes marked by different PTMs affect gene expression and nuclear architecture, enabling durable epigenetic memory across multiple cell generations.
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