Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression.
Molecular chaperone heat-shock protein 90 kDa (Hsp90) is known to facilitate the conformational maturation of a diverse range of proteins involved in different signal transduction pathways during development. Recent studies have implicated Hsp90 in transcriptional regulation and an important role for Hsp90 in epigenetic processes has been proposed. Importantly, genetic and pharmacological perturbation of Hsp90 was shown to reveal heritable phenotypic variation and Hsp90 was found to play an important role in buffering genetic and epigenetic variation whose expression led to altered phenotypes. The underlying molecular mechanism remains elusive, however. Here, we show a direct molecular interaction between Hsp90 and Trithorax (Trx). Trx is a member of the TrxG chromatin proteins controlling, together with the members of the Polycomb group, the developmental fate of cells by modulating epigenetic signals. Hsp90 cooperates with Trx at chromatin for maintaining the active expression state of targets like the Hox genes. Pharmacological inhibition of Hsp90 results in degradation of Trx and a concomitant down-regulation of homeotic gene expression. A similar effect is observed with the human orthologue mixed-lineage leukemia. Connecting an epigenetic network controlling major developmental and cellular pathways with a system sensing external cues may explain the rapid fixation and epigenetic inheritance of phenotypic variation as a result of impaired Hsp90.
Tariq
Muhammad
M
Department of Biosystems Science and Engineering, Eidgenössiche Technische Hochschule Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
Nussbaumer
Ute
U
Chen
Yujie
Y
Beisel
Christian
C
Paro
Renato
R
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017344:Genes, Insect; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D063146:Polycomb-Group Proteins; D055550:Protein Stability; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C512571:trx protein, Drosophila