Gene expression had been very straightforward for a decade. Genes were either reported switched on or off but not both. Then in 2006, a blockbuster finding revealed that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes. These genes were referred to as bivalently marked genes. They can potentially be committed to one way or another during development and differentiation.
After extensive research, it has been postulated that the control regions or promoters of some genes stay “poised” for plasticity. These genes are particularly critical for development during the undifferentiated state and their promoters do so by communicating with both activating and repressive histones. This state of genes is biologically termed as bivalency.
Researchers at the Stowers Institute for Medical Research had published research in the journal Nature Structural and Molecular Biology which identifies the protein complex that implements the activating histone mark specifically at poised genes in mouse embryonic stem (ES) cells. Furthermore, the study reports that its loss has little effect on developmental gene activation during differentiation. Thus, the study suggests that there is more to learn about the interpretation of histone modification patterns in embryonic and even cancer cells.
It has been previously known that promoters of developmentally regulated genes exhibit both the stop and go signals. This supports the idea that histone modifications could constitute a code that regulates gene expression and is not absolute but context dependent.
In 2001, a complex of yeast proteins called COMPASS was characterized for the first time. It enzymatically methylates histones in a way that favors gene expression. Mammals have six COMPASS look-alikes, two SET proteins (1A and 1B) and four MLL (Mixed-Lineage Leukemia) proteins. The latter is named so because they are mutant in some leukemias.
Comprehending the results
The basic topic of the study was the role of mouse Mll2 in establishing bivalency. The primer of the genes defines three potential methylation states of histone H3. If lysine i.e. the 4th amino acid displays three methyl groups (designated H3K4me3), then it signifies active transcription from that region of the chromosome.
If the 27th residue of histone H3, which is also a lysine, is trimethylated (H3K27me3), it marks the association with the silencing of that region of the chromosome. However, if both histone H3 residues are marked by methylation (H3K4me3 and H3K27me3 marks), that gene is deemed poised for activation in the undifferentiated cell state.
It was already known that an enzyme complex called PRC2 implements the repressive H3K27me3 mark. In order to identify which COMPASS family member is involved in this process, researchers genetically eliminated all the possibilities and came up with Mll2 as the responsible factor.
The researchers evaluated the behaviors of Mll2-deficient mouse embryonic stem cells. The cells continued to display self-renewal ability. However, when cultured with a factor that induces their maturation, Mll2-deficient mouse embryonic stem cells showed no apparent abnormalities in gene expression.
This means that Mll2-deficient mouse ES cells that receive a differentiation signal can still activate genes required for maturation, even though they have lost the H3K4me3 mark on bivalent regions.
This study paves the way for understanding what is the real function of bivalency in pluripotent cells and development. The findings of the study also potentially impact oncogenesis. The tumor-initiating cancer stem cells exhibit bivalent histone marks at some genes. This study enumerates how cancer stem cells from a tumor or suggest a way to shut these genes down.