Biology

Dr. Ritwick Sawarkar
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

Epigenetic mechanisms play a critical role in generating phenotypes from genotypes. The chaperone heat shock protein 90 (HSP90) is thought to buffer genetic variation by stabilizing proteins with variant sequences, thus uncoupling phenotypes from genotypes. In our work, we find an unexpected role of HSP90 in buffering cis-regulatory variation affecting gene expression. By employing an epigenetic pathway HSP90 represses the regulatory influence of endogenous retroviruses (ERVs) on neighboring genes critical for mouse development. Harnessing natural variations in the mouse genome, our data show that genes are responsive to HSP90 inhibition
depending on their genomic location vis-à-vis 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 novel regulatory layer through which HSP90 uncouples phenotypic outcome from individual genotypes, with implications for personalized medicine.