ABSTRACT Hsp90 is a specialized molecular chaperone that is capable of buffering the expression of abnormal phenotypes. Inhibition of Hsp90 activity results in the expression of these

phenotypes that are otherwise masked. Selection of offspring from the crossing of affected progenies results in inheritance and enrichment of these phenotypes, which can become independent

of their original stimuli. The current combined evidence favours a model involving the interplay between genetics and epigenetics. The recent proteomics efforts to characterize the Hsp90

interaction networks provide further clues into the molecular mechanisms behind this complex phenomenon. This review summarizes the most recent experimental observations and briefly

Article Open access 18 January 2024 STRUCTURAL AND FUNCTIONAL COMPLEXITY OF HSP90 IN CELLULAR HOMEOSTASIS AND DISEASE Article 31 July 2023 INTRODUCTION Hsp90 is an abundant and highly

conserved ATP-dependent molecular chaperone that is well characterized with respect to its function 1, its physical and genetic interactors 2, 3, and its influence on phenotypic expression

4. Hsp90 is distinct from other chaperone systems in two main aspects. Unlike the regular chaperone systems, Hsp90 does not act to fold non-native proteins, but rather binds to substrate

proteins that are in a near-native state and, thus, which are at a late stage of folding 5. Furthermore, Hsp90 seems to be a specialized chaperone that targets a specific set of client

proteins that are mainly involved in signal-transduction pathways. Hsp90 substrates include many transcription factors and protein kinases 6. The _in vivo_ and _in vitro_ activity of Hsp90

depends on its association with cochaperones, such as Hsp40 and Hsp70, and cofactors, such as p23 (yeast Sba1) and Hop (yeast Sti1), that are components of the large Hsp90-multiprotein

complexes involved in folding client proteins. Cochaperones regulate the Hsp90 ATPase activity, assist in protein folding, or function as a scaffold for Hsp90 complexes 7. Several

small-molecule drugs, such as geldanamycin and radicicol 8, 9, have been discovered that specifically inhibit Hsp90 ATPase; these drugs bind in the ATP-binding pocket at the N-terminal

domain of the chaperone 10. 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 non-Mendelian 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. Since Hsp90 is highly conserved across many different species, it is reasonable to expect that the general features of a similar Hsp90 interaction

network and the possible functional linkage between the chaperone and the chromatin remodelling complexes will also be conserved. This review provides a summary of the most recent research

in this area. HOW TO EVOLVE? In natural selection, changes in the environment drive the selection for phenotypes that are adaptive, and the fixation of selected phenotypes gives rise to new

traits. In classical evolution, phenotypes are determined by the corresponding genotypes that arise from non-deleterious mutations or recombinations of genes, which produce adaptive

genotypes that are favoured and, therefore, positively selected (Figure 1A). This selection leads to preservation of 'useful' genes in the population's gene pool, while

'useless' genes are lost in the selection process (Figure 1A). In addition, genetic drift, which is defined as random changes in allele frequencies in the offspring population due

to the imperfect genetic representation of the parental population, is also likely to play a part in removing rare genes from the population. The effect of genetic drift would be more

pronounced if the population size is small. An alternative mechanism was proposed in CH Waddington's developmental canalization model 14, 15. The model states that, in the wild

population, there are masked phenotypes that can be expressed by environmental perturbations. Selection for adaptive phenotypes over several generations results in their fixation, and the

resulting phenotypes become the new traits for the population. The model has two important features. (1) The 'new' phenotypes are inducible by environmental stress and are inherent

to the population, and they do not entail any changes to the population's genome. (2) Positive selection for these phenotypes over several generations results in their fixation and

independence from the original stimuli that was required for their initial expression; in other words, the phenotypes become 'canalized'. There is evidence that supports the

inheritance of different modification states of DNA from one generation to the next 16, 17, 18, 19. Since these modifications lead to changes in gene expression profile, this suggests that

epigenetics, which is defined as the inheritance of the changes in gene expression profile without alterations in the genomic sequence, should also be considered as part of the evolutionary

equation, at least in terms of phenotypic plasticity. Established epigenetic factors include DNA methylation 17, chromatin remodelling 16, 18, 19, histone modification 17, 18, and RNA

interference (RNAi) 20. In other words, changes in the DNA sequence of an organism's genome might not be required to alter its phenotype and the development of a new trait through

natural selection might be, in part, the result of epigenetic variations (Figure 1B). PHENOTYPIC BUFFERING BY HSP90 The buffering of stress-induced phenotypes by Hsp90 has been studied in

several different organisms. Rutherford and Lindquist 11 showed that genetic and pharmacological impairment of Hsp90 in _Drosophila melanogaster_ (fruit flies) produces abnormal phenotypes

that are enhanced at mildly higher or lower than normal temperatures. Phenotypic selection of a wing or an eye phenotype by crossing affected progenies for several generations resulted in an

increase of their frequencies as well as in the divergence of each phenotype. In addition, distribution of affected individuals varied between different inbred lines. Similarly, progenies

from wild-type flies crossed to _Hsp83_ mutants (gene encoding Hsp90 protein in _Drosophila_) as well as geldanamycin- (an Hsp90 inhibitor) treated flies also showed a similar increase in

morphological phenotypes, thus showing that the phenotypic buffering by Hsp90 is naturally occurring 11. Several important observations were made in these experiments. First, the acquired

phenotypes generated by Hsp90 impairment became independent of Hsp90 after successive inbreeding between affected individuals. PCR genotyping revealed that affected progenies from the F6 and

F7 generations no longer possessed the original _Hsp83_ mutation that induced the abnormal phenotype 11. Second, the increase in affected progenies did not occur in a Mendelian fashion.

More than 80% of the F6 and F7 generations were affected when only 66% was expected. The authors explained these observations as the result of the involvement of multiple genetic

determinants. Third, the phenotypic buffering capacitance of Hsp90 in fruit flies harbouring the _Hsp83_ mutation was compromised when compared to wild-type strains. Similarly, flies

harbouring _Hsp83_ mutations were more sensitive to environmental perturbations such as abnormal growth temperatures. Moreover, the number of affected individuals expressing abnormal

phenotypes upon exposure to geldanamycin was much larger in _Hsp83_ mutant strains as compared to wild-type strains. Because Hsp90 is highly conserved across species, it comes as no surprise

that phenotypic buffering by Hsp90 was also observed in the plant _Arabidopsis thaliana_ (mouse ear cress). Queitsch _et al._ 12 observed that pharmacological inhibition of Hsp90 by

geldanamycin or radicicol, two structurally and chemically dissimilar drugs 8, 9, produced similar spectra of abnormal phenotypes within a given inbred line. Different lines displayed their

own unique spectra of these phenotypes. Similar to _Drosophila_, plants exposed to higher than normal growth temperature (27 °C) were able to induce the same spectra of abnormal phenotypes

in almost all of the inbred lines. Furthermore, it was found that the dark response, which is an adaptation for growing in the dark and an example of phenotypic plasticity, showed varying

Hsp90 dependencies among the different inbred lines. One important observation is that the Hsp90-buffered phenotypes in _Arabidopsis_ did not affect the plant's vitality and overall

fitness; rather, some of these phenotypes, such as altered leaf morphology and purple pigment accumulation, might actually be beneficial depending on the environment. These findings in

_Arabidopsis_ further reinforce the idea that Hsp90 buffers phenotypic variation. INTERPLAY BETWEEN 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 chromatin state by affecting global histone

H3 acetylation levels, which was suggested to be responsible for epigenetic inheritance of eye phenotype. The eye outgrowth phenotype was found to be reversed by histone deacetylase (HDAC)

inhibitors like trichostatin A and sodium butyrate. Interestingly, mutations in some trithorax group genes like _verthandi_ (_vtd__3_) also induced the same eye phenotype in the same

sensitized fly line. Importantly, after out crossing the _verthandi_ mutation, the phenotypic selection of individuals with an ectopic eye outgrowth resulted in an increase in the number of

affected progenies in successive generations. Upon exposure to geldanamycin, an identical phenotype was also observed in an isogenic fly line that did not harbour the _vtd__3_ mutation.

Phenotypic selection for this drug-induced phenotype produced an increase in its frequency in successive generations that were not treated with geldanamycin. Similarly, expression of the

phenotype in the geldanamycin-treated sensitized fruit flies became independent of the drug as early as the F1 generation. Evidence that relates the above observations to chromatin

acetylation states came from modified selection experiments. In these experiments, F6 fruit flies, selected for the geldanamycin-induced _vtd__3_ phenotype, were fed trichostatin A and

sodium butyrate. It was found that both HDAC inhibitors were able to suppress the _vtd__3_ phenotype by two- to three-fold magnitudes. Similar phenotypic suppression was also observed in

_Hsp83_ and original _vtd__3_ mutants. These data provide strong evidence that heritable chromatin acetylation states are associated with Hsp90-induced phenotypic inheritance. However, the

exact molecular mechanism and link between Hsp90 and trithorax or Hsp90 and epigentics remains elusive. INHERITANCE OF PHENOTYPES INDUCED BY HSP90 INHIBITION 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. In characterizing the

inheritance of the deformed eye phenotype in _Drosophila_, Rutherford and Lindquist 11 mapped the hereditary determinants to at least two variants on the second chromosome, which are in turn

dependent on the presence of others on the third chromosome. Hsp90 itself was found not to be the hereditary determinant for the phenotype, as revealed by the lack of _Hsp83_ mutation in

the affected progenies of later generations. In _Arabidopsis_, Queitsch _et al._ 12 reported that the dependence of phenotypic plasticity on Hsp90 activity was not the result of an Hsp90

polymorphism. For example, the phenotypic variation in hypocotyl elongation, one of the characteristic traits of dark response, did not map to the cytoplasmic Hsp90 gene cluster. If Hsp90 is

not responsible for phenotypic inheritance, what might be the possible underlying mechanism of the process? Both the studies from the Lindquist laboratory 11, 12 proposed that the

phenomenon is genetic in nature. They proposed that the inheritance and increase of the Hsp90-dependent phenotypes is the result of enrichment of multiple genetic determinants. For example,

in _Drosophila_, the second and third chromosomes were required to sustain the deformed eye phenotype since heterozygosity in either one of the chromosomes with a control chromosome resulted

in a marked reduction in phenotypic inheritance 11. In _Arabidopsis_, differences in phenotypes, generated by geldanamycin treatment, are less dramatic between the different recombinant

inbred (RI) lines than between the parental lines from which the RI lines were generated 12. Furthermore, the exact spectra of phenotypes displayed upon inhibition of Hsp90 were dependent on

the genetic background of the inbred line 12. At the same time, there is evidence that supports the involvement of epigenetic elements in the inheritance of Hsp90-induced phenotypes. It has

been proposed that specific DNA methylation and chromatin modifications, which might be functionally linked to Hsp90, are epigenetic mechanisms by which patterns of gene activity and

silencing are inherited without any changes to the genomic sequence 4, 15, 21 (Figure 2). For example, CARM1 (coactivator-associated arginine methyltransferase 1), which participates in

histone H3 arginine-17 methylation, associates with estrogen receptor (ER) and plays an important role in transcription regulation. ER is regulated by Hsp90 such that the presence of

estrogen induces release of ER from Hsp90, and the ligand-bound ER then activates transcription of specific genes 22. As another example, SMYD3 (SET- and MYND-domain containing 3), the human

histone H3 lysine-4 methyltransferase, requires Hsp90 for optimal activity. SMYD3 is in turn required for the activation of WNT genes (coined after the _wingless_ gene in _D.

melanogaster_), which are involved in a complex pathway governing changes in cell behaviour and morphogenesis in normal organ development and in tumours. The inheritance and enrichment of

Hsp90-induced phenotypes is indeed a very complex phenomenon. Whether a given phenotype would be inheritable after its induction depends on many different variables: the biochemistry

involved in the production of the phenotype, the identities of the genes and gene products involved, the effect of specific genetic backgrounds, the subsequent requirement of the original

stimuli that resulted in the phenotype, and others. But perhaps one of the most important determinants is the stability of the inheritance. As pointed out by Sangster _et al._ 23, the

instability of an epigenetic event due to the reversibility of biochemical modifications on DNA and/or histones would present problems in the maintenance of any altered chromatin states from

one generation to the next. Thus, a stable inheritance of the phenotype requires the interplay between genetics and epigenetics. While the rapid production of the phenotype upon Hsp90

inhibition could be accounted for by epigenetic events, phenotypic selection would lead to the accumulation of relevant genetic determinants that serve to canalize the phenotype. THE GLOBAL

HSP90 INTERACTION NETWORK: IMPLICATIONS FOR PHENOTYPIC INHERITANCE A recent integrated proteomic and genomic study of the Hsp90 interaction network in _S. cerevisiae_ (budding yeast)

revealed that the chaperone interacts physically and/or genetically with 10% of the yeast proteome/genome 3. The study was based on a combination of four complementary experimental

strategies. First, systematic genome-wide screens were carried out for protein-protein interactions mediated by Hsp90 using a two-hybrid technique based on ordered strain arrays 24. Second,

protein mass spectrometry to identify proteins that copurify with Hsp90 in tandem affinity purification (TAP) procedures were carried out. In this procedure, Hsp90 or yeast ORFs were

chromosomally TAP-tagged 25 and the tag was used to pull down Hsp90-containing complexes. Third, synthetic lethal interactions between a temperature-sensitive mutant allele of Hsp90 and

members of a panel of ∼4700 single yeast gene deletion strains were identified using the synthetic genetic array technology 26. Lastly, the deletion mutant strains were screened for

differential hypersensitivity to the Hsp90 inhibitor geldanamycin in liquid culture using a microarray-based readout 27. In this study, 198 putative physical interactors and 451 genetic

interactors of the chaperone were uncovered. These putative interactors included established Hsp90 cofactors (e.g. Cns1, Cpr6, Cpr7, and Ppt1) and cochaperones (e.g. Ssa1 and Sti1). Several

transcription factors (e.g. Adr1, Aft2, Cha4, Gln3, etc.) and protein kinases (e.g. Cdc15, Cka2, Ctk1, Snf1, etc.) were also identified as interacting with the chaperone, suggesting roles

for Hsp90 in multiple signalling pathways. Importantly, several components of the INO80 and SWR-C chromatin remodelling complexes were also shown to interact with Hsp90. These include the

DNA helicases Rvb1 and Rvb2 (components of both INO80 and SWR-C complexes), Aor1 (component of the SWR-C complex), Swr1 (component of the SWR-C complex, ATPase of the SWI/SNF family), Vps71

(component of the SWR-C complex), Ies1 (subunit of the INO80 chromatin remodelling complex), as well as the H2A histone variant, Htz1/H2A.Z 3. Furthermore, novel cofactors of Hsp90, termed

Tah1 and Pih1, that link Hsp90 to the Rvb1 and Rvb2 DNA helicases were identified in this study. Hence, this detailed analysis of global Hsp90 interactors in yeast strongly suggests a

functional linkage between Hsp90 and the chromatin remodelling machinery. It is reasonable to speculate that the general features of such a network will be conserved in higher organisms.

Previous studies on SWR-C revealed its specificity in exchanging the core histone dimer H2A-H2B for H2A.Z-H2B (H2A.Z being a variant of H2A) in the nucleosomes of euchromatin (Figure 2C),

thereby preventing the spread of neighbouring heterochromatin (Figure 2E) 28. When entire nucleosomes in the parent chromatin are disassembled (Figure 2F and 2G), CAF-1 (chromatin assembly

factor 1), which is part of the replication-dependent histone chaperone complex specific for the S-phase H3 histone 29, 30, carries a single H3-H4 dimer 29 to be delivered back to one of the

two DNA replicates during re-assembly (Figure 2H and 2I) 28. CAF-1 might function with another H3-H4 chaperone ASF1 (anti-silencing function 1) 30. The redistribution of parental H3

histones, which carry with them specific covalent modifications, serves to transfer part of the parent's epigenome into the chromatin of each daughter cell. Other mechanisms, yet to be

identified, might subsequently reconstruct the missing half of the transferred epigenome, using the parental half as the template 28. Thus, as suggested by the proteomics work discussed

above, the activity/inactivity of Hsp90 might affect SWR-C-dependent chromatin remodelling and, hence, could affect the chromatin state that is inherited by the chromatin in each daughter

cell (Figure 2A-2E). This could be extrapolated to explain the effect of HDAC inhibitors in suppressing phenotypic inheritance as observed by Sollars _et al._ 13, since inhibiting histone

deacetylation prevents the spread of heterochromatin, which allows the maintenance of parental chromatin states and their inheritance (Figure 2B). This scenario, which is similar to a

hypothetical mechanism proposed by Sangster _et al._ 23, allows for an explanation of an epigenetic effect of Hsp90 function. Other scenarios involving different molecular mechanisms have

also been proposed 23. CONCLUDING REMARKS Hsp90 functions as a capacitor for phenotypes that are normally suppressed. Their expression via Hsp90 inhibition, genetically, pharmacologically,

or by mild environmental perturbations, reveals a molecular mechanism for changing gene expression patterns in response to the environment. Depending on the organism's lifestyle, the

expression of abnormal phenotypes can be advantageous in adapting to new environmental conditions. The Hsp90-induced phenotypes in _Drosophila_ and _Arabidopsis_ discussed here display

phenotypic inheritance and enrichment when affected progenies are inbred. The process is likely the result of the interplay between genetics and epigenetics. Considering the stability of

phenotypic inheritance associated with the accumulation of genetic determinants, and that different genetic backgrounds harboured different spectra of these phenotypes 11, 12, genetics is

definitely one of the major determinants. At the same time, the fact that gene mutations are not required to maintain the abnormal phenotypes 13, the interaction of Hsp90 with chromatin

remodelling complexes 3, and the effect of chromatin acetylation states on the stability of phenotypic inheritance 13, all indicate a significant role for epigenetics. Owing to the large

number of factors required, the different pathways involved to produce particular phenotypes, and the complex interactions between genetics and epigenetics, it is likely that the inheritance

of different Hsp90-induced phenotypes might employ different genetic-epigenetic mechanisms for their expression and subsequent maintenance. Further investigation is required for a better

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Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Jamie Snider (Department of Biochemistry, University of Toronto, Toronto, Canada) and Dr Muhammad Tariq (Centre

for Molecular Biology, University of Heidelberg, Heidelberg, Germany) for careful reading of the manuscript. Work in the corresponding author's laboratory is supported by research

grants from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and the National Cancer Institute of Canada. AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, M5S 1A8, Ontario, Canada Keith SK Wong & Walid A

Houry Authors * Keith SK Wong View author publications You can also search for this author inPubMed Google Scholar * Walid A Houry View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Walid A Houry. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wong, K., Houry, W.

Hsp90 at the crossroads of genetics and epigenetics. _Cell Res_ 16, 742–749 (2006). https://doi.org/10.1038/sj.cr.7310090 Download citation * Published: 29 August 2006 * Issue Date: 01

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