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Revealing the Cyclical Control of Stem Cell Bivalency

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Review of “Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency” from Stem Cell Reports by Stuart P. Atkinson.

The bivalent domains that exist in pluripotent stem cells (PSCs) are the chromatin version of Janus, the ancient roman God with two faces who was able to look into the past and the future at the same time. In the chromatin context, the two faces of Janus are represented by two normally opposing chromatin modifications; trimethylation of lysine K4 histone H3 (H3K4me3) which enhances gene expression and trimethylation of lysine K27 histone H3 (H3K27me3) which acts to restrict gene expression. Bivalent domains form specifically on developmentally-associated genes in PSCs, where the two opposing histone modifications act to “poise” gene expression, ready for boost transcription if the cell differentiates, or to repress transcription if the cell decides to remain pluripotent [1, 2].

The initial formation and the regulation of bivalent domains are, however, relatively unknown and therefore we still do not fully understand the molecular underpinnings of PSC differentiation. But now, a new study from the laboratory of Stephen Dalton (University of Georgia, USA) in Stem Cell Reports has reported that bivalent domains are unexpectedly dynamic and their formation is controlled by cell cycle regulators [3].

The lab found that bivalent domains, previously assumed to be static and unchanging in pluripotent stem cells, are actually very dynamic in nature, and their exact makeup changes throughout the cell cycle. While the restrictive H3K27me3 modification remains at all stages of the cell cycle, the permissive H3K4me3 appears and disappears in a cyclical manner. Specifically, H3K4me3 increases during the G1 cell cycle phase to place differentiation-associated genes in a poised transcriptional state, and this finding correlates well to studies which found that stem cells only differentiate in the G1 cell cycle phase [4]. Pluripotency-associated genes and housekeeping genes did not show any cyclical changes in H3K4me3, suggesting that this mode of regulation is specific to developmentally-associated gene regulation.

So why only in G1? Well the researchers found that the enzyme responsible for making the H3K4me3 modification, the MLL2/KMT2B methyltransferase, is phosphorylated and activated by the G1-S phase-specific cell cycle regulator Cyclin Dependent Kinase 2 (CDK2). Activation of MLL2 by CDK2 therefore targets the histone-modifying enzyme to developmental genes only in G1-S, where it aids the formation of bivalent domains and also enhances the formation of the promoter-enhancer loops required for the expression of differentiation associated genes.

This new study provides fresh insight into the mechanisms that lie behind pluripotency and differentiation, although the authors do note that not all developmentally-associated gene are regulated in this manner, suggesting that another layer of control remains to be discovered. 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 extends to mediate multipotency and the differentiation of adult stem cell populations.

References

  1. Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006;125:315-326.
  2. Mikkelsen TS, Ku M, Jaffe DB, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007;448:553-560.
  3. Singh AM, Sun Y, Li L, et al. Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency. Stem Cell Reports 2015;5:323-336.
  4. Singh AM, Chappell J, Trost R, et al. Cell-cycle control of developmentally regulated transcription factors accounts for heterogeneity in human pluripotent cells. Stem Cell Reports 2013;1:532-544.