Genes that code for some developmental regulators in embryonic stem cells (ESCs) might be excused if they seem a little confused. The regulatory signals they receive from their enveloping histone environment are a combination of “Stop!” and “Go!” signals for their transcription. Although this seems counterintuitive, this combination of modifications, known as a bivalent domain, allows stem cells to react quickly to either remain stem cells (self-renew) or differentiate into another lineage when required.
But what causes this fuzzy undecidedness? Alcohol-induced indifference? Drug-related mania? No, it turns out that something more sedate is to blame – cycling! But put away the spandex and the helmets, we are only interested in the “cell cycle” – the repeated events that take place in a cell leading to its division and duplication.
A new study into bivalent domains, the cell cycle, and stem cells from the laboratory of Stephen Dalton (University of Georgia, USA), published in Stem Cell Reports, has shown for the first time that:
- Bivalent domains are dynamic in nature and change during the cell cycle.
- H3K4-trimethylation increases during a specific cell cycle phase (G1) to promote gene expression.
- Bivalent domains only form at this stage, allowing stem cells to express developmental genes and differentiate if given the molecular go-ahead.
- This agrees with previous data demonstrating that stem cells only differentiate in G1. Eureka!
- The MLL2/KMT2B methyltransferase enzyme, which adds H3K4-trimethylation, is phosphorylated and activated by the cell cycle regulator CDK2 in G1.
- Activation by CDK2 targets MLL2 to developmental genes to form a bivalent domain and to re-organize the histone environment into a state ready for transcription.
This provides fresh insight into the fundamental mechanisms that lie behind pluripotency and the differentiation of stem cells, although the authors do note that not all developmentally-associated gene are regulated in this manner, suggesting another layer of control. They also hope to discover if demethylases are also regulated in a cell cycle-regulated manner to erase H3K4-trimethylation and if this mode of regulation also exists in adult stem cells.
As always, there is more to discover, but get into gear with these new findings first – Stem Cell Reports, August 2015.