Aberrant Silencing of Ribosomal DNA Initiates a Global Stress Response that Promotes H3K9‐mediated Adaptation

Abstract

The covalent modification of histones establishes distinct phenotypic or epigenetic states without altering the underlying genetic code. This process allows cells to respond to acute changes in cellular homeostasis resulting from alterations in intracellular, environmental, or metabolic conditions. The consequences of post‐translational modifications of histones are multifaceted, leading to the emergence of chemotherapy resistance in cancers, drug resistance in fungal pathogens and temperature‐dependent initiation of flowering in plants. One modification, histone H3 lysine 9 methylation (H3K9me), is associated with heterochromatin formation, and under conditions of acute stress, heterochromatin relocates to silence novel genes that enhance cellular fitness. It is still a mystery how cells activate this adaptive pathway and mark specific genes with H3K9me to successfully adapt to adversity. We find that, in S. pombe cells, adaptive H3K9me is preceded by activation of a global stress response and downregulation of ribosome biogenesis machinery. Our results indicate that aberrant silencing of the ribosomal DNA repeats triggers adaptation via H3K9me and allows cells to respond to complex stresses by developing novel heritable phenotypes. My completed work provides me unprecedented temporal resolution into H3K9me adaptation and sets the foundation for investigation of more complex questions involving the H3K9me adaptive process.