A core Klf circuitry regulates self-renewal, according to a Nature Cell Biology paper.

A group of researchers have found that one of four reprogramming factors used last year to persuade human skin cells to revert to an embryonic stem-cell state is dispensable in ES cells. Klf4, a transcription factor that determines whether a cell’s genes are active or silent, has at least two other molecules that will substitute Klf4 to maintain a pluripotent embryonic stem-cell state, the scientists explain.

“Klf4 has been a mysterious player among the four reprogramming factors,” notes Genome Institute of Singapore (GIS) scientist Ng Huck Hui, Ph.D., who headed the research team. “As taking out Klf4 in ES cells did not have any apparent effects, it is difficult to reconcile why such a potent reprogramming factor has no role in ES cell biology.”

Klf4 belongs to the Krüppel-like factor (Klf) family of transcription factors that regulate numerous biological processes including proliferation, differentiation, development, and apoptosis.

The research team found that when Klf4 was depleted, Klf2 and Klf5 took over Klf4’s role. To understand the molecular basis of the Klf4 redundancy, the scientists studied the DNA binding and transcription activation properties of the three Klfs and found that the profiles of all were similar.

“Most important, the data showed that the other Klfs were bound to the target sites when one of them was depleted,” says Dr. Hui. “These Krüppel-like factors form a very powerful alliance that work together on regulating common targets. The impact of losing one of them is masked by the other two sibling molecules.”

For example, Klfs were found to regulate the Nanog gene and other key genes that must be active for ES cells to be pluripotent. “We suggest that Nanog and other genes are key effectors for the biological functions of the Klfs in ES cells,” Dr. Hui reports. “Our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression that is unique to ES cells.”

GIS led the research, which also included investigators the National University of Singapore, Nanjing Medical University, and University of Illinois at Urbana-Champaign. The study appears in the current issue of Nature Cell Biology.

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