The Stem Cell Epigenome
Stem cells have the potential to differentiate into multiple cell types. As Conrad Waddington had suggested, a stem cell can be thought of as a ball on top of the hill with high potential energy and as this ball rolls down the hill it attains a stable minima. The opposite of this process is called reprogramming wherein you go from this differentiated state to a stem cell state. Eventhough these cells are so different, both transcriptionally and phenotypically (i.e. they have different gene expression profiles and different functions), they share the same DNA sequence. Therefore, these functional differences may be linked with both molecular and structural changes in the genome that don’t change the underlying DNA sequence.
The unique combination of molecular and structural modifications which constitute the epigenome alter the likelihood of expression of genes leading to different phenotypes in stem cells. The epigenome is this layer of information that sits on top of our genome, and it determines which genes will be expressed for a given cell type to perform its functions. In other words, the epigenome dictates the bone cell to turn ON genes to make proteins required for its functions and those responsible for a heart cell’s function to be turned OFF. This is the reason why a heart cell beats but a bone cell does not even though they share the same DNA sequence. DNA methylation (which affect DNA directly) and histone modifications (which affect the DNA indirectly) are among some of the molecular modifications that modulate gene expression. In addition to molecular modifications, the structural modifications are also an important predictor of transcriptional and phenotypic plasticity in stem cells. When it comes to structural aspects of the epigenome we can think of the chromatin organization, which is DNA wrapped around proteins called histones packed differentially at different length scales. Altogether, epigenetic chnages are much like analog signals that can result in a spectrum of transcriptional outcomes based on the combination of modifications that are added to/removed from the gennome unlike genetic changes which are binary or digital in nature.
A stem cell can be thought of as a Rubik’s cube with different chromatin domains as well as molecular modifications, represented by each small colored cube. The stem cell epigenome is highly plastic, and the pieces of the cube can be moved around allowing distinct domains or genomic regions and combinations of molecular modifications to come together and consequently creating different functional states (cell types). As the stem cell differentiates, this flexibility to move the pieces of the Rubik’s cube around decreases. In other words, inherent plasticity in a stem cell is reduced as it reaches a stable differentiated state.
Vasundhara Agrawal
My research interests include Chromatin Engineering and Cell Reprogramming.