title: The evolutionary capacitor HSP90 buffers the regulatory effects of mammalian endogenous retroviruses.
abstract: Understanding how genotypes are linked to phenotypes is important in biomedical and evolutionary studies. The chaperone heat-shock protein 90 (HSP90) buffers genetic variation by stabilizing proteins with variant sequences, thereby uncoupling phenotypes from genotypes. Here we report an unexpected role of HSP90 in buffering cis-regulatory variation affecting gene expression. By using the tripartite-motif-containing 28 (TRIM28; also known as KAP1)-mediated epigenetic pathway, HSP90 represses the regulatory influence of endogenous retroviruses (ERVs) on neighboring genes that are critical for mouse development. Our data based on natural variations in the mouse genome show that genes respond to HSP90 inhibition in a manner dependent on their genomic location with regard to strain-specific ERV-insertion sites. The evolutionary-capacitor function of HSP90 may thus have facilitated the exaptation of ERVs as key modifiers of gene expression and morphological diversification. Our findings add a new regulatory layer through which HSP90 uncouples phenotypic outcomes from individual genotypes.
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hummel
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Hansen
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Aneliya
authors.initials: A
authors.lastname: Yoveva
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Fernando
authors.initials: F
authors.lastname: Aprile-Garcia
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hussong
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Ritwick
authors.initials: R
authors.lastname: Sawarkar
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D004251:DNA Transposable Elements / Q000235:genetics; D020077:Endogenous Retroviruses / Q000378:metabolism*; D019143:Evolution, Molecular; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D008322:Mammals / Q000235:genetics*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058977:Molecular Sequence Annotation; D016254:Mutagenesis, Insertional / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28