Researchers from the University of Manchester say they have identified an important trigger that dictates how cells change their identity and gain specialized functions. The believe their study (“Otx2 and Oct4 Drive Early Enhancer Activation during Embryonic Stem Cell Transition from Naive Pluripotency”), published in Cell Reports, has brought them a step closer to being able to decode the genome.

The scientists have found out how embryonic stem cell fate is controlled, which will lead to future research into how cells can be artificially manipulated. Lead author Andrew Sharrocks, Ph.D., professor in molecular biology, said: “Understanding how to manipulate cells is crucial in the field of regenerative medicine, which aims to repair or replace damaged or diseased human cells or tissues to restore normal function.”

During the research the team focused on an enhancer, which controls the conversion of DNA from genes into proteins. Different enhancers are active in different cell types, allowing the production of distinct gene products and hence a range of alternative cell types. In the current study, the team have determined how these enhancers become active.

“We know a lot about the complex transcriptional control circuits that maintain the naive pluripotent state under self-renewing conditions but comparatively less about how cells exit from this state in response to differentiation stimuli. Here, we examined the role of Otx2 in this process in mouse ESCs and demonstrate that it plays a leading role in remodeling the gene regulatory networks as cells exit from ground state pluripotency,” wrote the investigators. “Otx2 drives enhancer activation through affecting chromatin marks and the activity of associated genes. Mechanistically, Oct4 is required for Otx2 expression, and reciprocally, Otx2 is required for efficient Oct4 recruitment to many enhancer regions. Therefore, the Oct4-Otx2 regulatory axis actively establishes a new regulatory chromatin landscape during the early events that accompany exit from ground state pluripotency.”

“All of us develop into complex human beings containing millions of cells from a single cell created by fertilization of an egg,” said Dr. Sharrocks. “To transit from this single cell state, cells must divide and eventually change their identity and gain specialized functions. For example we need specific types of cells to populate our brains, and our recent work has uncovered the early steps in the creation of these types of cells.”

According to Dr. Sharrocks, one of the most exciting areas of regenerative medicine is the newly acquired ability to be able to manipulate cell fate and derive new cells to replace those that might be damaged or lost, either through old age or injury. “To do this, we need to use molecular techniques to manipulate stem cells, which have the potential to turn into any cell in our bodies,” he explained.
But one of the current drawbacks in the field of regenerative medicine is that the approaches are relatively inefficient, partly because scientists do not fully understand the basic principles that control cell fate determination.

“We believe that our research will help to make regenerative medicine more effective and reliable because we'll be able to gain control and manipulate cells, thus our understanding of the regulatory events within a cell shed light on how to decode the genome,” concluded Dr. Sharrocks. 

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