Key Regulator of Cell Differentiation Identified

Embryonic stem cells and other pluripotent cells divide rapidly and are capable of becoming virtually any cell type in the body. Scientists have long sought to understand the signals that cause stem cells to rule out pluripotency and accept their ultimate functional state.

In a study published in Proceedings of the National Academy of Sciences, researchers report that they have identified a key regulator of this process. They found that a molecule known as BEND3 stops the expression of hundreds of genes involved in differentiation, maintaining stem cell-like status. Only when BEND3 is lowered can cells take on their final shape and function. Once they differentiate, they usually stop actively reproducing.

The findings are relevant to an understanding of normal development and may also be useful in cancer research, said Illinois professor of cell and developmental biology Urbana-Champaign and head of the department Supria Prasant, who led the study.

“In most cancers, cells go through this rapid proliferation because the regulators of the cell cycle do not work properly,” she said. “Predicting how cancer cells will respond to treatment is often related to their differentiation status. The more differentiated the tumor, the better the prognosis. ”

Prosant said stem cells are capable of inhabiting a cancerous tumor after it has shrunk during treatment. Finding a molecular switch that will shift cancer cells from proliferation to differentiation can help treat cancer.

Prosanta Laboratory focuses on cell cycle regulators. Her early research identified BEND3 as a potentially important player in the system. Her team found that when BEND3 linked to strategic sites along a chromosome, it reduced or blocked the expression of dozens of genes. When BEND3 was removed, gene expression was restored.

“If you do these gene expression studies, you can see hundreds of genes up, hundreds down,” Proshant said. “But what does that really mean?”

In a new study, she and her colleagues found that many genes repressed by BEND3 promote cell differentiation. Postgraduate students from Illinois Freddy Courniavan and Neha Chetlangi led the work with graduate student Mohammad Kamran in collaboration with the Laboratory of VI Cells and Professor of Developmental Biology Kannananattu Prosanta and Mirita Aladjem, senior researcher at the National Institutes of Health. institute.

“Binding of BEND3 to these genes blocks their expression, preventing cells from entering a differentiated state,” said Supria Proshant. “And the moment you remove that control, the cells are now moving toward a path of differentiation.”

BEND3 is not the only regulator of cell differentiation pathways; it binds to and interacts with many other molecular regulators of the process, Supria Prasant said. But its presence or absence seems crucial to determining the fate of a cell, making it an attractive target for potential medical interventions if the process goes wrong.

In an accompanying article published in the journal Genes and Development, the Supria Prasant Laboratory and the staff of the Sloan Kettering Memorial Cancer Center gave a structured view of gene regulation mediated by BEND3.

Help: Prasanth S et al. BEND3 provides pluripotency by suppressing genes associated with differentiation. PNAS. 2022; do: 10.1073 / pnas.2107406119

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