DNA Methylation Generates Differential Gene Expression in Sister Stem Cells

Despite having identical DNA, sister embryonic stem cells (ESCs) can display considerable differences in their molecular characteristics. How stem cells regulate expression of their genes is crucial to many fundamental biological processes, such as embryonic development, regeneration, and turnover of blood, skin, and other tissues in the body, but especially to cancer.

In a study published in the September 26, 2013, online edition of the journal Stem Cell Reports investigators at the Institute of Cancer Research (London, United Kingdom) used a novel microdissection technique to examine differences in expression of 48 key genes between sister stem cells.

Their system, which was based on single cell RNA analysis, revealed considerable diversities between sister ESCs at both pluripotent and differentiated states. When the stem cells were grown in the presence inhibitors that induced the cells to revert to their most primitive stem cell state, gene expression between sister cells was significantly more similar.

DNA methyltransferases were downregulated in the inhibited ESCs, and the loss of these enzymes was sufficient to generate nearly identical sister cells. These results suggest that DNA methylation was a major cause of the diversity between sister cells at the pluripotent states. DNA methylation stably alters the expression of genes in cells as they divide and differentiate from embryonic stem cells into specific tissues. The resulting change is normally permanent and unidirectional, preventing a differentiated cell from reverting back to a stem cell or converting into another type of tissue.

Senior author Dr. Tomoyuki Sawado, leader of the stem cells and chromatin team at The Institute of Cancer Research, said, "Embryonic stem cell division is generally believed to be a symmetrical process, but what we found was that sister cells are actually often quite different from one another. We used a new technique to separate paired stem cells combined with assays that measure RNA in individual cells. Our research showed that sister stem cells display considerable differences in which genes are expressed. These differences are advantageous for normal stem cells in their constantly changing environment, and in cancer cells, the same characteristics can enable them to evade treatments. If we can control a process like DNA methylation that creates diversity in cell populations, we could create more efficient treatments for cancer."

Related Links:
The Institute of Cancer Research