Modeling how cells choose their fate

Credit: Ronghui Zhu, Ellowitz lab, Caltech

It may seem hard to believe, but each of us started out as a single cell that multiplied into the trillions of cells that make up our bodies. Although each of our cells has exactly the same genetic information, each also performs a specialized function: neurons control our thoughts and behaviors, for example, while immune cells learn to recognize and fight diseases, skin cells protect us from the outside world, and muscles It enables cells to move, etc.

All of these types of cells have a common origin called pluripotent stem cells. Full of possibilities, stem cells are like a blank slate that can become any type of cell. By analogy, consider how a child grows into an adult and choose his career path. How stem cells choose their occupations depends on complex chains of interactions within the cell’s genome (its DNA), called epigenetic circuits.

Now, researchers in the lab of Michael Elwitz, professor of biology and bioengineering and a Howard Hughes Medical Institute investigator, have developed an artificial genetic circuit that demonstrates how cells can choose their fate. The research is described in a paper published in the journal Science On January 20.

Using this circuit, which they called MultiFate, the researchers demonstrated how a relatively small set of protein components and interactions is sufficient to create and control a larger number of cellular states through a property called “multistability.” MultiFate now enables researchers to engineer a single living cell that can change into different states that are each stable on their own but capable of performing a distinct function – similar to what happens in our own bodies.

Cells with the synthetic MultiFate circuit can exist in 7 different cell states, or “fates”, each making the cell glow a different color (red, green, blue, yellow, magenta, cyan or white). Here, we see many cells, all genetically identical and growing in the same environment, but present in different MultiFate states. MultiFate ensures that cells remember their fate as they grow and divide, making all cells in a given colony maintain the same color. Credit: Ronghui Zhu, Ellowitz lab, Caltech

Led by graduate student Ronghui Zhu, the researchers engineered an artificial circuit of genes that could operate inside cells grown in a lab without interfering with normal cellular processes. The MultiFate circuit consists of three genes, each encoding a conformational transcription factor (a protein that expresses genes) labeled with a distinct color protein: red, green or blue. Each of these three proteins turns itself on by binding to its DNA. The three types of proteins can stick to each other to prevent each other’s activity.

As the team’s mathematical model predicted, this type of circuit could allow a cell to exist in up to seven distinct states. Like the pixels on a computer screen, each of these states expresses a different set of red, green, and blue proteins, causing cells to glow in any of seven different colors: red, green, blue, cyan, white, purple, or yellow. Once it is in one of these states, the cell remains in it unless the researchers deliberately disturb it. Because cells are locked into their fate, the cell transfers its fate (its color) to its dependent cells as it grows and divides.

In addition, in contrast to normal cellular circuits, which are difficult to control, the researchers designed MultiFate so that they could induce the cell to switch between the seven states using specific drugs.

“This work demonstrates how designing and building artificial circuits from scratch can provide insights into fundamental biological phenomena. MultiFate is inspired by the properties of natural cell fate control circuits but is designed from the bottom up. It not only helps explain how cells reside in So many fates, it could also provide a basis for expanding cellular therapies to take advantage of multiple cell types to perform more complex therapeutic functions that no single cell type can provide,” says Ellowitz.

The title of the paper is “Structural pluralism in mammalian cells”. Chu is the paper’s first author. In addition to Zhu and Ellowitz, the co-authors are Caltech graduate student Jesus M. Del Rio Salgado and Jordi Garcia-Ogalvo of Pompeu Fabra University in Barcelona, ​​Spain.

Circuits dedicated to living cells

more information:
Ronghui Zhu et al, Compositional pluralism in mammalian cells, Science (2022). DOI: 10.1126 / science.abg9765

Presented by the California Institute of Technology

the quote: Modeling How Cells Choose Their Fate (2022, January 21) Retrieved January 21, 2022 from

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