Bivalent chromatin are segments of DNA, bound to histone proteins, that have both repressing and activating epigenetic regulators in the same region. These regulators work to enhance or silence the expression of genes. Since these regulators work in opposition to each other, they normally interact with chromatin at different times. However, in bivalent chromatin, both types of regulators are interacting with the same domain at the same time. Bivalent chromatin domains are normally associated with promoters of

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

genes that are expressed at low levels. Bivalent domains have also been found to play a role in developmental regulation in

pluripotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

embryonic stems cells, gene imprinting and

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

Bivalent epigenetic regulators

The most common antagonistic epigenetic regulators found together on bivalent chromatin domains are

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

marks on histone 3 lysine 4 (

H3K4me3 H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the add ...

) and histone 3 lysine 27 (

H3K27me3 H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein. This tri-methylation is associated with the Downregulation and upregulation, dow ...

). The H3K27me3 mark silences the gene while the H3K4me3 mark allows the gene to not be permanently silenced, and activated when needed. Embryonic stem cells and imprinted genes are associated with both activating (H3K4me3) and repressive (H3K27me3) marks, as they allow a gene to be repressed until activation is needed. Although there is abundant evidence for co-localization of H3K4me3 and H3K27me3 at the same location in the genome, most evidence suggests that they do not occur on the same molecule but may occur on different copies of

histone H3 Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a stri ...

within the same

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...

Embryonic stem cells and development

Bivalent chromatin domains are found in embryonic stem (ES) cells and play an important role in cell differentiation. When keeping an ES cell in its undifferentiated state, bivalent domains of DNA are used to silence developmental genes that would activate cell differentiation, while keeping the genes poised and ready to be activated. When an ES cell receives a signal to differentiate into a specified cell lineage, activation of the specific developmental genes are needed for differentiation. The developmental genes needed will be activated and the other genes that are not required for that cell lineage will be repressed through their bivalent domains. H3K4me3 and H3K27me3 marks found on the bivalent domains regulate whether or not an embryonic stem cell differentiates or remains unspecified (pluripotent state). The epigenetic marks contribute to the expression of some genes, and silencing of others during

pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

and differentiation. H3K27me3 marks repress developmental control genes and stop the cell from differentiating, to ensure that the cell maintains pluripotency. Although this mark represses the lineage control genes, it does keep them ready for activation upon differentiation. When the cell receives the signal to differentiate to a specific type of cell, H3K27me3 will be removed from the genes needed for differentiation, while H3K27me3 maintains repression of developmental control genes that are unnecessary for the chosen lineage. The developmentally regulated process of resolving bivalent chromatin is aided by the activity of ATP-chromatin remodelers such as

SWI/SNF In molecular biology, SWI/SNF (SWItch/Sucrose Non-Fermentable), is a subfamily of ATP-dependent chromatin remodeling complexes, which is found in eukaryotes. In other words, it is a group of proteins that associate to remodel the way DNA is packa ...

, which hydrolyze ATP to evict

Polycomb-group proteins Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox gene ...

from bivalent chromatin. Only a specific subset of regulators will be activated by H3K4me3 to give a certain cell lineage. This mark activates developmental regulators upon differentiation, and makes the genes needed for differentiation more efficient. Having the activating H3K4me3 mark protects genes from being silenced permanently by repelling transcription repressors and blocking repressive DNA methylation. Once the cell has differentiated to a specific type of cell only one of the marks remain associated with the chromatin.

Imprinting

Imprinting is the process by which one parental allele is silenced while the allele from the other parent is expressed. The human ''GRB10'' gene displays imprinted gene expression, and in mice, this imprinted Grb10 expression is enabled by the presence of bivalent chromatin. The Grb10 gene in mice has a bivalent domain that uses H3K4me3 and H3K27me3 modifications as a tool to express genes from one parent while the other is silenced. This allows the gene to be expressed by only one parent in a specific tissue. In most somatic tissues, the Grb10 gene is expressed from the maternal allele, except in the brain where it is expressed from the paternal allele. H3K4me3 and H3K27me3 marks are used on the paternal allele of the gene to keep it silenced in all tissues except the brain. The same methylation marks are used on the maternal allele of the gene in brain tissue. When the genes are being expressed the H3K27me3 repressive mark is removed from the bivalent domain.

References

{{DEFAULTSORT:Bivalent Chromatin Molecular genetics