'Rogue' protein chooses own path in maintaining embryonic stem cells
By Ruth SoRelle, M.P.H.
A ronin is a samurai without master or lord – often outlawed from his clan and choosing his own path.
That name seemed appropriate for a protein identified by Thomas Zwaka, M.D., Ph.D., assistant professor in the Stem Cell and Regenerative Medicine Center at Baylor College of Medicine and the department of molecular and cellular biology at BCM. In fact, that’s why he chose it.
The path of Ronin
The protein Ronin goes its own way in maintaining embryonic stem cells in their undifferentiated state, he said in a report in the journal Cell. It also plays an essential role in the production and development of embryos.
The discovery of Ronin adds to knowledge about the regulator of embryonic stem cells. Before, scientists had considered three other proteins – Oct4, Sox2 and Nanog – the
"master" regulators of embryonic stem cells.
"Ronin could be as important as these three," said Zwaka. In fact, he said, Ronin can compensate when Oct 4 – the most important regulator – is reduced in the embryonic stem cells.
What are embryonic stem cells?
Scientists call embryonic stem cells pluripotent. By that, they mean that such cells can differentiate into almost every other kind of cell in the body, and they can renew themselves, maintaining a state in which they can be called upon to differentiate. Oct4, Sox2 and Nanog were previously thought to be the major factors involved in the renewal of embryonic stem cell populations.
Ronin takes a different path
Zwaka said Ronin represents a different and parallel pathway to maintain this population of cells. Ronin is also expressed in early embryonic development of mice. If it is not present, the embryos die, said Zwaka. It is also found in mature oocytes or egg cells.
"Ronin is a potent transcription repressor," he said. In fact, it prevents the action of genes that promote the differentiation of cells into the various tissues and organs of the body.
"It does it more effectively than the other three factors together," he said. It silences the differentiation genes epigenetically through specific chemical mechanisms that modify histones, the chief packaging proteins for DNA. Zwaka and his colleagues found Ronin as a follow-up to an earlier study that showed a component of the cell death system called caspase-3 actually cleaved and reduced the amount of Nanog protein. This caused the embryonic stem cells to stop self-renewal and begin differentiation into other kinds of cells.
Zwaka and his colleagues searched for other proteins affected by the caspase and found Ronin, which was previously unknown.
More questions
The finding prompts other questions. Can Ronin be used to reprogram differentiated cells into those that more closely resemble embryonic stem cells? What is the significance of the portion of Ronin that resembles a "jumping gene" or transponson called P element transposase, usually found in the genomes of fruit flies?
Ronin is also found in areas of the brain such as the hippocampus and the Purkinje cells of the cerebellum.
Others who took part in this research include Marion Dejosez, Joshua S. Krumenacker, Laura Jo Zitur, Marco Passeri, Li-Fang Chu and Zhou Songyang, all of BCM and James A. Thomson of the University of Wisconsin at Madison.
Funding for this research comes from the Lance Armstrong Foundation, the Gillson Longenbaugh Foundation, the Tilker Medical Research Foundation, the Diana Helis Henry Medical Research Foundation, the Huffington Foundation and the National Institutes of Health.
