Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution

Abstract

Morphological alterations have been shown to occur in Drosophila melanogaster when function of Hsp90 (heat shock 90-kDa protein 1alpha, encoded by Hsp83) is compromised during development. Genetic selection maintains the altered phenotypes in subsequent generations. Recent experiments have shown, however, that phenotypic variation still occurs in nearly isogenic recombinant inbred strains of Arabidopsis thaliana. Using a sensitized isogenic D. melanogaster strain, iso-Kr(If-1), we confirm this finding and present evidence supporting an epigenetic mechanism for Hsp90's capacitor function, whereby reduced activity of Hsp90 induces a heritably altered chromatin state. The altered chromatin state is evidenced by ectopic expression of the morphogen wingless in eye imaginal discs and a corresponding abnormal eye phenotype, both of which are epigenetically heritable in subsequent generations, even when function of Hsp90 is restored. Mutations in nine different genes of the trithorax group that encode chromatin-remodeling proteins also induce the abnormal phenotype. These findings suggest that Hsp90 acts as a capacitor for morphological evolution through epigenetic and genetic mechanisms.

Hsp90 at the crossroads of genetics and epigenetics

“…Similar to studies from Lindquist's lab [11], it was recently reported that impairment of Hsp90 activity in flies either by genetic mutation or pharmacological inhibition resulted in inheritance of a specific eye phenotype in an isogenic fly line [13]. However, in contrast, an epigenetic basis for capacitor function of Hsp90 was revealed by the finding that depletion of Hsp90 induced an altered …”

“…Although there is clear evidence that phenotypes induced by Hsp90 inhibition are heritable and can be fixed by phenotypic selection [11][12][13], the exact mechanism of the inheritance process remains unclear. Several lines of evidence suggest that phenotypic variations induced by Hsp90 inhibition become independent of the chaperone after they are inherited across successive generations.…”

“…Recently, it has been found that Hsp90 inhibition in several model organisms induces the inheritance and enrichment of abnormal phenotypes [11][12][13]. By inbreeding the affected progenies for successive generations, the frequencies of the abnormal phenotypes increase in a nonMendelian fashion.…”

“…To date, there is no definitive molecular model for explaining this experimental phenomenon. While some evidence currently available would favour a genetically based model [11,12], other evidence seems to better suit an epigenetically based model [13]. In this regard, a recently published integrated proteomic and genomic study of the Hsp90 interaction network in Saccharomyces cerevisiae [3] revealed putative physical and genetic interactions between Hsp90 and several components of the INO80 and SWR-C chromatin remodelling complexes strongly suggesting a functional linkage between Hsp90 and the chromatin remodelling machinery, at least in yeast.…”

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

“…34 The effect of GA on Caspase 8 expression in neuroblastoma has not been reported, but work in Drosophila has shown that compromise of Hsp90 function can alter gene expression through effects on chromatin remodeling factors. 35 In future work, it will be interesting to see whether GA exposure restores Caspase 8 expression in neuroblastoma cells, thus contributing to the induction of apoptotic death in this tumor type.…”