The Bivalent Genome: Characterization, Structure, and Regulation

Gene promoters and enhancers are decorated in each cell type by precise combinations of histone marks according to their current transcriptional status. Bivalent promoters have both histone H3 trimethylated on lysine 4 (H3K4me3) and H3K27me3 marks, thereby preparing key developmental genes to be rapidly switched on during differentiation (from a silenced to transcriptionally active state) exclusively in specific cell types. H3K4me3 and H3K27me3 exhibit distinct cell cycle patterning: H3K4me3 is restored before mitosis and displays cell cycle oscillation, whereas H3K27me3 is restored after mitosis and remains constant. Bivalent domains, which are chromatin regions co-occupied by H3K4me3 and H3K27me3, exhibit a particular 3D conformation in embryonic stem cells that becomes redistributed during differentiation. Poised enhancers, which are characterized by the presence of both H3K4me1 and H3K27me3, likely play a key role during differentiation, similarly to bivalent promoters. Bivalency is a chromatin property that is tightly linked to the pluripotent state of stem cells in mammals. However, recent findings suggest that they in fact represent a universal mechanism for tissue-specific gene regulation. Coincidence between bivalent domains in pluripotent stem cells and aberrant methylation patterns of the same regions in cancer intriguingly suggests that bivalency could be utilized as a promising marker of tumorigenesis. An intricate molecular machinery is at the core of gene expression regulation in every cell. During the initial stages of organismal development, the coordinated activation of diverse transcriptional programs is crucial and must be carefully executed to shape every organ and tissue. Bivalent promoters and poised enhancers are regulatory regions decorated with histone marks that are associated with both positive and negative transcriptional outcomes. These apparently contradictory signals are important for setting bivalent genes in a poised state, which is subsequently resolved during differentiation into either active or repressive states. We discuss the origins of bivalent promoters and the mechanisms implicated in their acquisition and maintenance. We further review how the presence of bivalent marks influences genome architecture. Finally, we highlight the potential link between bivalency and cancer which could drive biomedical research in disease etiology and treatment. An intricate molecular machinery is at the core of gene expression regulation in every cell. During the initial stages of organismal development, the coordinated activation of diverse transcriptional programs is crucial and must be carefully executed to shape every organ and tissue. Bivalent promoters and poised enhancers are regulatory regions decorated with histone marks that are associated with both positive and negative transcriptional outcomes. These apparently contradictory signals are important for setting bivalent genes in a poised state, which is subsequently resolved during differentiation into either active or repressive states. We discuss the origins of bivalent promoters and the mechanisms implicated in their acquisition and maintenance. We further review how the presence of bivalent marks influences genome architecture. Finally, we highlight the potential link between bivalency and cancer which could drive biomedical research in disease etiology and treatment. regions of genome that are covered by two histone modifications (generally H3K4me3 and H3K27me3) that can potentially lead to either activation or silencing of transcription. gene promoter regions decorated by H3K4me3 and H3K27me3. a series of stages comprising two gap phases (G1 and G2), an S phase (in which DNA replication takes place), and an M phase (in which the cell divides, producing two daughter cells). large-scale sequencing of ChIP libraries to determine a genome-wide map of sites that are characterized by transcription factor binding or association with specific histone marks. an experimental technique to determine, using specific antibodies, whether a fragment of DNA is bound by a particular protein or is associated with a histone modification. a large-scale technology that combines ChIP of histone marks with purification of newly replicated DNA followed by next-generation sequencing to track the propagation of epigenetic states across cell division. ATP-dependent proteins that modify chromatin accessibility either by compacting the chromatin (associated with transcriptional repression) or by chromatin opening (associated with transcriptional activation). complex of proteins associated with Set1, a family of Trithorax multiprotein complexes that methylate lysine 4 on histone H3 (H3K4me) in the chromatin. histones undergo distinct chemical modifications of an amino acid in the histone tail, which are associated with activation or repression of transcription. physical contacts between two distant regions of chromosomes. Interactions can occur between functional regions such as promoters and enhancers. the addition of a methyl group to a nucleotide base (mostly in cytosines) in DNA. This is an alternative epigenetic mechanism to that reported for histone modifications, and is generally associated with gene transcription repression. pluripotent stem cells derived from the inner cell mass of a blastocyst in early mammalian embryos. These cell lines are able to differentiate into every embryonic cell type while retaining their self-renewal ability. hereditary information that is key for gene regulation, and that is encoded in chromatin structure rather than in the DNA sequence. the basic unit of DNA packaging, comprising a DNA molecule wrapped around eight histone protein cores (H2A, H2B, H3, and H4 dimers). Different histone variants have been reported for H2A (e.g., H2A.Z and H2A.X) and H3 (H3.3). a distal genomic regulatory region decorated by H3K4me1 and H3K27me3. a chromatin state of functional regions (e.g., promoters or enhancers) that has marks of both repression and activation (i.e., differs from purely repressed states); a poised state allows rapid activation in response to distinct developmental inputs. a family of proteins that catalyze methylation of lysine 27 on histone H3 (H3K27me) as well as ubiquitination of histone H2A on lysine 119 (H2Aub); they are mostly associated with chromatin compaction and gene silencing. PRC1 is a Polycomb multiprotein complex that catalyzes the ubiquitination of H2A (H2Aub), whereas PRC2 methylates lysine 27 on histone H3 (H3K27me) in the chromatin. large-scale sequencing of sequential ChIP libraries to delineate a genome-wide map of co-occurrences of two proteins or histone marks. double ChIP reactions to confirm the co-occurrence of two proteins or histone marks at the same locus, in which the first ChIP product (e.g., the chromatin bound by the first antibody) is tested for recognition by a second antibody directed against the second protein/mark of interest. a family of proteins that can deposit and/or recognize the mark H3K4me (methylation of lysine 4 on histone H3), among others; this mark is mostly associated with active promoters/enhancers and bivalent regions. sequence-specific DNA-binding transcription factors that bind to DNA and regulate the expression of genes by interacting with and recruiting RNA polymerase complexes.