Gene bookmarking: keeping the pages open

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‘Gene bookmarking’ is a mechanism of epigenetic memory that functions to transmit through mitosis the pattern of active genes and/or genes that can be activated to daughter cells. It is thought that, at a point before mitosis, genes that exist in an open, transcriptionally competent state are bound by proteins or marked by some kind of modification event. This is thought to facilitate the assembly of transcription complexes on the promoters in early G1, thereby ensuring that daughter cells have the same pattern of gene expression as the cell from which they derived. Little is known, however, about these ‘bookmarking factors’ and modifications or the mechanisms by which they mediate the transmission of transcriptional competence after mitosis is complete. Recent findings have provided new insights into the mechanisms, regulation and biological importance of gene bookmarking in eukaryotic cell function.

Introduction

Cells have several mechanisms for regulating transcription that are based on modulation of chromatin structure near specific genes. These mechanisms include remodeling of chromatin by enzymes such as histone deacetylases that are recruited to promoter regions by DNA-binding factors 1, 2, 3, 4, 5, differential methylation of specific DNA regions to mediate the allele-specific expression of genes called in a process termed ‘genomic imprinting’ [6], and binding of insulator proteins at specific locations in chromosomes to prevent the migration of chromatin states or transactivation between neighboring chromosomal sites 7, 8. There is, however, another mechanism that is crucial for proper gene expression – termed gene bookmarking – about which much less is known.

To maintain the phenotype of cell lineages, cells must have a way to remember which genes are active before cell division and to propagate that pattern through mitosis to daughter cells. The problem is that during mitosis most sequence-specific DNA-binding proteins are thought to dissociate from the DNA, making it difficult to understand how such information could persist through this part of the cell cycle. As an explanation for this phenomenon, it has been proposed that before the onset of mitosis all active genes are somehow ‘marked’, so that the daughter cells know to reassemble the transcription machinery on the promoters of these genes. Because its proposed function is reminiscent of the way in which a bookmark marks the position of the last read page of a book, this mechanism has been given the name ‘bookmarking’, and the factors or modifications that mark the active genes have been called ‘molecular bookmarks’ [9]. The precise nature of these molecular bookmarks, and the mechanism by which they propagate patterns of gene expression through mitosis, has, however, largely remained a mystery.

Another proposed function of bookmarking, which seems to apply to a subset of bookmarked genes, is to endow specific genes that must be able to be activated in the early G1 phase of the cell cycle – such as the hsp70 gene that is crucial for protection from cellular stress – with the ability to re-establish quickly transcription competence on their promoters as soon as the general mitotic repression of transcription ends. According to this proposition, if such genes were not bookmarked the cell might not be able to transcribe from the gene promoters until the normal decompaction process was complete, which would perhaps delay transcription competence until later in G1. For the hsp70 gene, such a delay might leave the cell unable to induce protective heat shock proteins in response to stresses occurring in G1, potentially leading to disruption of cell function or even cell death. Similarly, bookmarking a gene such as c-myc might be important for its expression, which in turn is necessary for the proper control of cellular growth.

In this review, we focus on recent advances in how bookmarking is mediated at the molecular and biochemical level, in addition to the importance of this mechanism for cell function.

Section snippets

Unusual structure of promoter regions in mitotic cells

For the proper segregation of chromosomes into daughter cells, chromosomal DNA must be compacted during mitosis before cytokinesis. A protein complex called Condensin is important in this process of mitotic chromosomal compaction 10, 11, 12, 13, 14. Condensin is composed of five subunits: two members of the structural maintenance of chromosomes (SMC) protein family, named CAP-C and CAP-E; and three other subunits called CAP-G, CAP-D2, and CAP-H. This complex is converted to an active form at

Mechanisms of gene bookmarking

The findings described support the hypothesis that the structural perturbations found in the promoters of active genes in mitotic cells are involved in ‘bookmarking’ these genes for reactivation in daughter cells. They do not, however, provide information on the mechanism or mechanisms responsible for causing these altered chromatin structures in mitotic cells.

At least four mechanisms of gene bookmarking have been described or postulated in the literature. The first two mechanisms – the

Concluding remarks and future perspectives

From the results described in this review, two important features of gene bookmarking emerge. First, it seems that there are at least two biological functions of bookmarking: one is the bookmarking of active genes to ensure transmission of phenotype through mitosis to daughter cells; the other is the bookmarking of genes that need to be expressed in early G1, such as the hsp70 gene, which must remain inducible for cells to survive stress. Second, and perhaps not surprisingly, more than one type

Acknowledgements

We apologize to colleagues whose work we could not cite directly because of space considerations. We acknowledge the support of grants from the National Institutes of Health to K.D.S (GM61053, GM64606) and to O.K.P.-S. (HD36879, HD41609).

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