A research team led by Dr. Jun-Yi Leu, an Associate Research Fellow at the Institute of Molecular Biology has discovered that the molecular chaperone Hsp90 can regulate non-genetic variation in response to environmental stress. This study was published in the journal Molecular Cell on April 11, 2013. The article was immediately recommended by Faculty of 1000 as being of special significance in its field.

　　In recent years, the importance of non-genetic phenotypic variation (or phenotypic noise) has gradually gained biologists’ attention. Phenotypic noise has been shown to impact diverse aspects of life, including virus infection, pluripotency of embryonic stem cells, organ development, immune response, cancer biology and adaptation strategies of microorganisms. However, our knowledge about the underlying mechanisms and its regulation is still quite limited.

　　The research team finds that when the activity of heat shock protein 90 (Hsp90) is compromised, a clonal yeast population reveals morphological heterogeneity, a proportion of cells switching to a filamentous form that has been previously suggested to be beneficial under certain hostile environments. Hsp90 is an important molecular chaperone that facilitates the maturation of a wide range of client proteins. Since its client proteins are broadly involved in signal transduction and gene regulation, previous studies have shown that Hsp90 affects diverse cellular processes including cancer formation.

　　In this study, the researchers further demonstrate that the morphological heterogeneity is driven by the dosage of a cyclin-dependent kinase Cdc28 and Cla4, a key regulator of septin formation. Low Hsp90 levels reduce Cla4 protein stability and trigger morphological changes in a sub-population of cells. More importantly, the observed morphological heterogeneity can be induced by environmental stress and provide a survival benefit to a population. Finally, they show that this Hsp90-dependent morphological heterogeneity is conserved in a wide range of yeast species covering 100 million years of evolution, suggesting that it may be a common mechanism allowing cells to cope with environmental stress.

　　These results provide the first example with the detailed molecular mechanism about how Hsp90 regulates non-genetic variation. In addition, it suggests that Hsp90 can act as another layer of regulation for non-genetic variation in response to environmental stresses. Since Hsp90 interacts with many key proteins involved in different functional networks and the function of Hsp90 is conserved from yeast to humans, it is quite possible that Hsp90 functions as a common regulator of non-genetic variations in various cellular processes. The complete article entitled “Hsp90 Regulates Non-genetic Variation in Response to Environmental Stress” is available at Molecular Cell website at:

http://www.cell.com/molecular-cell/abstract/S1097-2765(13)00090-7

　　First author of the article Yu-Ying Hsieh is a research technician at the Institute of Molecular Biology. Co-author Po-Hsiang Hung is a Ph.D. student of Genome and Systems Biology Program of National Taiwan University and Academia Sinica. Dr. Jun-Yi Leu is supported by the Career Development Award of Academia Sinica and the Frontier Science Grant of National Science Council.