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Genetic and Epigenetic Control of Stem Cell Fate

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One of the key characteristics of stem cells is their ability to keep the perpetual equilibrium between self-renewal and differentiation. A stem cell divides asymmetrically into another stem cell and a differentiating daughter cell that must successfully transition from multi- to unipotency, in addition to ...

One of the key characteristics of stem cells is their ability to keep the perpetual equilibrium between self-renewal and differentiation. A stem cell divides asymmetrically into another stem cell and a differentiating daughter cell that must successfully transition from multi- to unipotency, in addition to losing the potential for self-renewal. Coordinated transcription factor networks are prominent regulators of stem cell self-renewal and differentiation. Now it is becoming evident that in conjunction with transcription factors at least three epigenetic elements (chromatin structure, DNA methylation, and microRNAs) form a reciprocal regulatory circuit to maintain the balance between stem cell self-renewal, proliferation and differentiation during embryonic development and adult life.
Modifications that affect the chromatin structure of genes that control cell fate decisions and the maintenance of stem cell state must be flexible and reversible. Therefore, epigenetic regulation of developmental genes has been identified as an essential mechanism underlying the establishment and regulation of differentiation potential during development. Temporally and spatially synchronized gene regulation at the epigenetic level acts mostly as a negative control to restrain abnormal and stochastic initiation of differentiation. Epigenetic DNA marks are inheritable through cell divisions, however in response to differentiation-inducing cues these marks can be easily erased allowing developmental genes to be in a 'poised state'. On the other hand, once a cell is committed to accept a certain fate, permanent repression of developmental genes takes place (chromatin changes). In addition, recently it has been shown that epigenetic mechanisms, including DNA methylation and histone modifications also control the expression of small non-coding RNAs, miRNAs that in turn regulate the expression of epigenetic factors. This creates a complex epigenetics–miRNA regulatory network that is based on feedback-feedforward signaling, which allows to reduce transcriptional noise and fine-tune gene expression. Thus, circuitry between miRNAs and distinct components of the epigenetic pathways (such as DNA methylation, histone modification, repression by polycomb complexes) act together to regulate the entire gene expression profile and ensure the robustness of cell fate.
Insight into the functioning of components of the stem cell genetic and epigenetic regulatory associations is essential for the development of novel strategies to maintain stem cells, reprogram differentiated cells or direct differentiation of stem cells. In addition, aberrant interactions between these factors may promote transformation of adult stem cells into "cancer stem cells" and contribute to malignancy.


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