Research Highlight: Scientists determine how one protein helps ‘reopen’ closed-off genes to regulate stem cell development

A new study from the University of Michigan and University of Wisconsin-Madison has shed light on the mechanisms that allow adult stem cells to pause, and even reverse, their development into other cell types.

The findings, published Dec. 9 in Nature Communications, could offer new understandings to the field of regenerative medicine, which aims to generate new cells or tissue to restore proper function.   

Each stem cell has the potential to develop into the variety of cell types that tissues within the body might need. It does this by turning on and off various genes as it divides, through a process called differentiation. The result is one exact copy of the stem cell (to maintain the stem cell pool) and another cell that expresses a different set of genes enabling it to become a new type of cell.

In general, differentiation usually only runs in one direction: once a cell begins to specialize, it cannot become less differentiated. One major exception to this is the very first cell of an embryo. Embryonic stem cells must have the ability to eventually create every type of cell in the body — but that first cell starts as a combination of two very specialized cells. Before it can begin to grow and divide, that cell must be reprogrammed by turning off all the genes that make it specialized and activating genes that create a stem cell state.

While this reprogramming has been studied extensively in embryos, it is much less understood in the adult stem cells, which can divide into more limited cell types. A neuronal stem cell, for example, can differentiate into any type of nervous system cell, but it could not become a liver cell. 

“We want to understand how the very powerful reprogramming factors that function in the early embryo operate in later life stages, and whether they use the same mechanisms to open closed-off parts of the genome,” says Melissa Harrison, Ph.D., an associate professor of biomolecular chemistry at the U-W School of Medicine and Public Health a senior author of the study. “If we can determine how they work in these more specialized stem cells, that understanding will shed light on how misexpressed reprogramming factors can lead to cancer, and it may be useful in thinking about strategies to regenerate particular tissue cells.”

If we can determine how they work in these more specialized stem cells, that understanding will shed light on how misexpressed reprogramming factors can lead to cancer.
Melissa Harrison, Ph.D., U-W School of Medicine and Public Health

Using the powerful toolbox available for studies in the model organism Drosophila melanogaster (or fruit flies), the researchers investigated what drives the stem-cell fate in neuronal stem cells called neuroblasts. They found that one central player is at work in both embryonic and neuronal stem cells, but also identified key differences in the process.

A protein called Zelda is able to access parts of the genome that have become otherwise inaccessible and open those genes back up for activation. It does this by latching onto a specific sequence in the genome.

“If you think of the sequence like an address, Zelda is able to find the addresses that don’t appear on the map,” explains Cheng-Yu Lee, Ph.D., a faculty member at the U-M Life Sciences Institute and the Medical School and a senior author of the study. “What we found in the neuroblasts is that Zelda continues this function, but it’s finding completely different addresses than it visited in the embryo stage—finding different sequences to latch onto to open the genes in these different cell types.”

The researchers also demonstrated that excess Zelda activity in the cell can actually impede cell differentiation, preventing normal brain development and function in flies. When too much Zelda is present, cells begin to reverse their development into new nervous system cells, resulting in too many neuroblasts and resembling a tumor.

The findings identify Zelda as a key player in driving neuronal stem cell fate and verify that Zelda must be precisely regulated to establish the developmental program in both embryo and neuronal tissues.

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Top image: When expression of the protein Zelda is increased, larval fruit fly brains develop more neuronal stem cells, resulting in too many neuroblasts for proper brain function. Image shows larval brain lobes without (left) and with (center, right) overexpression of Zelda.

Disclosure & Authorship

This research was supported by the National Institutes of Health. Study authors are: Elizabeth D. Larson, Tyler J. Gibson, Danielle C. Hamm, Jack M. Schnell, and Melissa M. Harrison of the University of Wisconsin-Madison; and Hideyuki Komori, Cyrina M. Ostgaard, and Cheng-Yu Lee of the University of Michigan.

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