Bivalent histone modifications in early embryogenesis

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Histone modifications influence the interactions of transcriptional regulators with chromatin. Studies in embryos and embryonic stem (ES) cells have uncovered histone modification patterns that are diagnostic for different cell types and developmental stages. For example, bivalent domains consisting of regions of H3 lysine 27 trimethylation (H3K27me3) and H3 lysine 4 trimethylation (H3K4me3) mark lineage control genes in ES cells and zebrafish blastomeres. Such bivalent domains have garnered attention because the H3K27me3 mark might help repress lineage-regulatory genes during pluripotency while the H3K4me3 mark could poise genes for activation upon differentiation. Despite the prominence of the bivalent domain concept, studies in other model organisms have questioned its universal nature, and the function of bivalent domains has remained unclear. Histone marks are also associated with developmental regulatory genes in sperm. These observations have raised the possibility that specific histone modification patterns might persist from parent to offspring, but it is unclear whether histone marks are inherited or formed de novo. Here, we review the potential roles of H3K4me3 and H3K27me3 marks in embryos and ES cells and discuss how histone marks might be established, maintained and resolved during embryonic development.

Introduction

Histones are subject to various modifications, including methylation, acetylation, phosphorylation, ubiquitination and ribosylation [1]. These modifications alter protein–DNA and protein–protein interactions and regulate the interaction of transcriptional regulators with chromatin [2, 3] (see Box 1 for more information about chromatin and specific histone modifications). Immunofluorescence studies have revealed that global patterns of histone modifications and chromatin architecture change during the early stages of development [4, 5, 6•, 7, 8]. Genome-wide chromatin immunoprecipitation (ChIP) analyses have suggested that specific combinations of histone marks at promoters and enhancers correlate with the developmental potential and fate of cells [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21•, 22•, 23, 24]. For example, embryonic stem cells have a different histone modification landscape than cells with restricted fates [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21•, 22•, 23, 24]. The importance of these modifications in embryogenesis is highlighted by the severe phenotypes caused by mutations in histone-modifying complexes (see Table 1 for a summary of mouse and ES cell phenotypes [25, 26••, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46•, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58•, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75]). Here we review the potential roles of histone modifications during embryonic development with a focus on H3 lysine 27 trimethylation (H3K27me3) and H3 lysine 4 trimethylation (H3K4me3) marks at promoters in vertebrate embryos and embryonic stem cells.

Section snippets

Bivalent promoters in embryonic stem cells

Pluripotent cells from the inner cell mass of mammalian blastocysts can generate embryonic stem (ES) cells [76]. These cells are self-renewing and can give rise to all lineages of the developing organism (Figure 1). Pluripotency is maintained by the activity of a set of transcriptional regulators that include Nanog, Oct4 and Sox2 [77]. By contrast, transcriptional regulators that determine specific cell lineages are not expressed at significant levels in pluripotent cells. During

Bivalent promoters in embryonic cells

The identification of bivalent domains in permanently pluripotent ES cells (and potentially in differentiated cell types [11, 13, 81, 82, 83]) raises the question how relevant these findings are to transiently pluripotent cells in the embryo. Direct evidence for bivalent domains in vivo comes from studies in zebrafish: sequential ChIP has established H3K4me3/H3K27me3 co-occupancy of promoters in zebrafish blastomeres [84]. A study of mouse epiblast cells has also found putative bivalent

The function of H3K27me3 in bivalent chromatin domains – repression

It has been postulated that bivalently marked lineage-specific genes in ES cells are kept transcriptionally inactive by H3K27me3 [9, 10] (Figure 2A). Indeed, loss of components of Polycomb Repressive Complex 2 (PRC2) results in a loss of H3K27me3 and a partial derepression of genes that are normally bivalent and repressed [36, 45, 46•, 51]. It was initially proposed that H3K27me3-mediated repression of lineage regulators was essential for maintenance of ES cell pluripotency [45, 90]. However,

The function of H3K4me3 in bivalent chromatin domains – poising?

It has been postulated that bivalently marked lineage-specific genes in ES cells are kept transcriptionally poised by H3K4me3. In this model, the association of H3K4me3 with an inactive gene facilitates the future activation of that gene [9, 10] (Figure 2C). This putative function of H3K4me3 might extend beyond bivalent domains. For example, in Xenopus and zebrafish embryos and in ES cells, many inactive genes are marked with H3K4me3 in the absence of H3K27me3 [84•, 86•, 87•].

Despite its

Establishing H3K4me3 and H3K27me3 marks

How is the positioning of H3K4me3 and H3K27me3 marks directed? Several mechanisms could guide the de novo methylation of histones. For example, long non-coding RNAs can provide sequence specificity to Polycomb and Trithorax proteins [91, 92, 93, 94•, 95], or DNA binding proteins can recruit methyltransferases to specific sequence elements. Such elements might include Polycomb and Trithorax response elements [96, 97, 98] or CpG islands (genomic regions that contain a high frequency of mostly

Inheritance from sperm?

In embryos, it is not only unclear how H3K4me3 and H3K27me3 marks are established but also controversial when they first appear. Studies in human, mouse and zebrafish have shown that some developmental regulatory genes are already marked by H3K4me3 and H3K27me3 in sperm [102••, 103, 104]. It has been proposed that some of these marks are inherited after fertilization [86•, 102••, 103], but other studies have suggested that H3K4me3 and H3K27me3 marks are erased after fertilization and

Activation of lineage-specific genes

How do lineage regulators transition from an inactive state in ES cells to an active state during differentiation? In ES cells, many lineage regulators are inactive, associated with bivalent domains [9, 10, 11, 12, 13, 14] and occupied by pluripotency factors [9, 114, 115, 116, 117, 118]. It is thought that these factors recruit signal transducers [119], which then overcome H3K27me3-mediated repression and activate lineage-regulatory genes [9, 10, 11, 113•, 120, 121•, 122•, 123, 124]. For

Perspectives

There have been impressive advances in the genome-wide mapping of histone modifications and the phenotypic analysis of mutants that affect histone modifications. Novel concepts such as the bivalent poising of lineage regulators and the epigenetic inheritance from sperm have garnered wide attention. However, it remains poorly understood whether bivalency is a universally conserved principle across species, whether H3K4me3 truly poises genes for activation, and how parental histone marks can be

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Vincenzo Pirrotta and Leonie Ringrose for discussions and Brad Bernstein, Shelby Blythe, Brad Cairns, James Gagnon, Susan Mango, Andrea Pauli, John Rinn, Will Talbot, and Joanna Wysocka for helpful comments on the manuscript. NLV and AFS are supported by NIH grants 1K99HD067220-01 and 5RO1 GM056211, respectively. We apologize to colleagues whose work could not be discussed due to space constraints.

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    Present address: Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany.

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