Hsp90 and Epigenetic Canalization in Drosophila: Implications for Human Health

Douglas Ruden
Department of Environmental Health Sciences; University of Alabama at Birmingham

Rutherford and Lindquist demonstrated that morphological alterations occur in Drosophila melanogaster when Hsp90 function is compromised during development. They showed that genetic selection leads to the maintenance of the altered phenotypes in subsequent generations [1]. Using an "epigenetically sensitized" isogenic D. melanogaster strain, iso-KrIf, we presented an extension of this finding and propose an epigenetic mechanism whereby a decrease in Hsp90 activity induces a heritably altered chromatin state [2]. The altered chromatin state is evidenced by an abnormal eye phenotype, which is epigenetically heritable in subsequent generations, even when Hsp90 function is restored. Surprisingly, the penetrance of the epigenetic phenotype increases every generation in the selection experiment in the absence of genetic variation [2]. We propose that selection of "metastable epi-alleles" occurs and increase in number during the multi-generational epigenetic selection experiment [3]. Mutations in nine different trithorax-group genes that encode chromatin-remodeling proteins also induce the abnormal phenotype in a similar manner as Hsp90 [2]. Furthermore, new experiments show that mutations in genes encoding suppressors of position effect variegation, Su(var) mutations, suppress the epigenetic phenotype, whereas mutations in genes encoding enhancers of position effect variegation, E(var) mutations, enhance the epigenetic phenotype. We will also discuss new experiments that show that dietary soy can have long-term "metabolic imprinting" effects on body weight and triglyceride levels in Drosophila. Together, these experiments suggest that environment (diet and stress) can effect expression of "metastable epi-alleles," both within an organism's lifespan, and trans-generationally. If this occurs in humans, as we suspect, it has broad implications in human health and in the health of future generations. (Supported by NIH grants ES92133, CA105349 and the Soy Health Research Foundation)


  1. Rutherford, S.L. and S. Lindquist, Hsp90 as a capacitor for morphological evolution. Nature 396(6709): 336-342, 1998.

  2. Sollars, V., Ruden, D. M., et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33(1): 70-74, 2003.

  3. Ruden, D.M., Sollars, V., et al. Waddington\'s widget: Hsp90 and the inheritance of acquired characters. Semin. Cell Dev. Biol. 14(5): 301-310, 2003.