Master Key


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Dr. Elik Chapnik, Natali Rivkin and Dr. Eran Hornstein
It takes only a tiny key to open a door wide or set large machinery in motion. Dr. Eran Hornstein of the Weizmann Institute’s Molecular Genetics Department and his team recently discovered such a key – one that unlocks the cellular machinery for producing mature blood cells. That key is a minuscule, hairpin-shaped RNA belonging to a class of RNA strands so small they had long been ignored. Even now, these so-called microRNAs are too often thought to be secondary to the cell’s major processes. The new findings suggest that microRNAs can also be master keys, putting several vital processes into motion at once.

In collaboration with Prof. Steffen Jung of the Immunology Department and his coworkers Dr. Elik Chapnik, Natali Rivkin and Dr. Alexander Mildner, Hornstein discovered that a microRNA called miR-142 was involved in the process by which the immature cells in the bone marrow give rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells. In fact, an early hint for the importance of this microRNA had been documented years earlier, in 1989, as it plays a role in a type of B-cell leukemia. But back then, before the era of genomics and before the microRNA revolution, it was thought to be a protein-coding gene.


Wild type megakaryocyte
The Weizmann researchers looked at a broad lineage of myeloid cells – a group that includes the red blood cells and the platelets that make our blood clot. They were looking for cells in which miR-142 is instrumental, and that could provide a clear insight into its function. Their initial analysis pointed to megakaryocytes as the ideal experimental model.  

Megakaryocytes are very large cells in the bone marrow that generate platelets by budding off bits of their internal cytoplasm. The development of megakaryocytes and their ability to function as they mature depends on a strong, malleable internal structure – the cytoskeleton. In a series of experiments on mouse megakaryocytes, the researchers found that miR-142 is essential to the proper formation of the primary building material of the cytoskeleton – actin fibers. When miR-142 activity was halted, the production of actin was deregulated, and the megakaryocytes were not able to mature and produce platelets.
Megakaryocyte in which the microRNA mir-142 has been knocked out
Using a large array of techniques in their labs, the researchers were able to reveal the precise activities of miR-142. Their findings, which were recently published in eLife, show that miR-142 is, indeed, a master key that turns on and off a number of different cellular processes; these are crucial to actin production and regulation. To put it another way, microRNA-142 is a “hub” in the cellular network of pathways that keeps the cell growing, dividing, developing and functioning.  
According to Hornstein, the impact of microRNA-142 and its mechanism may even go all the way back to the first blood cells in the embryo. In addition, miR-142 malfunctions are likely to show up in certain clotting disorders; but the findings hint that the same miRNA gene may be involved in any number of other blood diseases. Hornstein: “This model for blood cell development is very informative and fruitful. Together with Jung we have already characterized four different cell types in which this miRNA is influential, which is very exciting.” 
The implications are clear for microRNA research, says Hornstein, helping cast microRNA in a new light: they can no longer be seen as mere helper molecules that “fine-tune” the cellular pathways; they are also key players with the power to direct the development of the cell.
Dr. Eran Hornstein’s research is supported by the Kekst Family Institute for Medical Genetics; the David and Fela Shapell Family Center for Genetic Disorders Research; the Crown Human Genome Center; the Yeda Sela Center; the Nella and Leon Benoziyo Center for Neurological Diseases; the Y. Leon Benoziyo Institute for Molecular Medicine; the Helen and Martin Kimmel Institute for Stem Cell Research; the Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; the Julius and Ray Charlestein Foundation; the Celia Benattar Memorial Fund for Juvenile Diabetes; the Wolfson Family Charitable Trust; the Legacy Heritage Fund; the Adelis Foundation; the Minna-James-Heineman Stiftung; Dr. Sidney Brenner and Friends; Maria Halphen, France; and the estate of Fannie Sherr. Dr. Hornstein is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair.

Prof. Steffen Jung’s research is supported by the Leir Charitable Foundations; the Leona M. and Harry B. Helmsley Charitable Trust; the Maurice and Vivienne Wohl Biology Endowment; the Adelis Foundation; Lord David Alliance, CBE; the Wolfson Family Charitable Trust; the estate of Olga Klein Astrachan; and the European Research Council.