What if we could make people young again? Or, if we could regenerate the human heart and treat heart ailments permanently? Cellular reprogramming could make it possible!
Cellular reprogramming can have several applications. It can help us model diseases much effectively, drug discovery, precision medicine and regenerative medicine. While understanding cellular reprogramming could be challenging for non-technical users, let us look at some basic terms that will help us understand cellular reprogramming much effectively.
Cellular reprogramming could guide cells to remodel their epigenetic marks. Image credit: Nissim Benvenisty via Wikimedia, CC-BY-2.5
What is Phenotype?
Phenotype refers to the observable characteristics or traits of an organism. It includes the organism’s physical form OR structure, its behavior, and the products of behavior.
What is Epigenetics?
Epigenetics is the study of heritable phenotype changes that do not involve alterations in the DNA sequence.
What is Cellular Reprogramming?
Reprogramming refers to the erasure and remodeling of epigenetic marks during mammalian development or in cell culture. Cellular Reprogramming has been discussed in the recent research paper by Yuuki Matsushita, Tetsuhiro S. Hatakeyama, and Kunihiko Kaneko titled “Dynamical-systems theory of cellular reprogramming” that forms the basis of the following text.
Importance of this research
The researchers have verified the possibility of cellular reprogramming by using a dynamical system model with a gene regulatory network (GRN) and epigenetic modification.
Understanding Cellular Differentiation
For simplicity, we can think of the Cellular differentiation process as balls falling down an epigenetic landscape. The balls start from the top of the landscape and fall into distinct valleys, corresponding to differentiated cell types. The position at the top is unstable(ball at the top), and the bottom (ball fallen into a distinct valley) position is comparatively stable.
What happens in cellular reprogramming?
In reprogramming, the cells need to move from a more stable state to a less stable one, i.e., from the bottom to the top of the landscape. This transition gives the cells regain the potentiality for differentiation, also referred to as pluripotency. Hence, cell reprogramming seems unintuitive.
DNA methylation is one specific case of cellular reprogramming in embryonic development in mammals.
About this Research
The gene regulatory networks randomly generated and those extracted from embryonic stem cells confirm the universality of cellular reprogramming. This transition is mathematically modeled with the help of the repressilator model, explained in detail in the research paper
Conclusion
In the words of the researchers,
In this letter, we have shown that oscillatory gene expression dynamics with slow epigenetic modifications lead to cellular reprogramming by overexpression of only few genes. The global attraction to the unstable manifold of the saddle point explains the reprogramming process. Now, the return to the top of the landscape by reprogramming, which is seemingly unstable, is explained by the strong attraction toward the unstable manifold of the saddle, and suppressed instability along with the unstable manifold, owing to the approach of limit-cycle of bifurcation to fixed points. The memory of the cellular state before reprogramming manipulation was erased through this reprogramming process. Moreover, regain of oscillation was found to be the main requirement for reprogramming, whereas elaborate manipulations to induce a cellular state into specific states is not necessary. This explains the role of oscillations in gene expression in pluripotent cells and epigenetic modification through the differentiation process, as well as it explains how reprogramming is possible by overexpressing just few genes among thousand of that. The timescale separation between fast expression dynamics and slow epigenetic modification feedback required is also consistent with previous observations. In future studies, experimental support is necessary, as well as theoretical analysis of slow-fast dynamical systems.
Source: Yuuki Matsushita, Tetsuhiro S. Hatakeyama, and Kunihiko Kanek’s “Dynamical-systems theory of cellular reprogramming”