A simple mechanism for epigenetic inheritance of silent chromatin.

Mechanisms enabling genetically identical cells to differentially regulate gene expression are complex and central to organismal development and evolution. While gene silencing pathways involving sequence-specific recruitment of histone-modifying enzymes are prevalent in nature, examples of sequence-independent heritable gene silencing are scarce. Studies of Schizosaccharomyces pombe indicate that sequence-independent propagation of heterochromatin can occur but requires numerous multisubunit protein complexes and their various activities. Such complexity has precluded a coherent articulation of the minimal requirements for heritable gene silencing by conventional approaches. Here, we take an unconventional approach to defining these requirements by engineering sequence-independent silent chromatin inheritance in Saccharomyces cerevisiae. The memory-conferring mechanism is remarkably simple and requires only two proteins, one that recognizes histone H3 methylation and deacetylates histone H4, and another that recognizes unmodified H4 and catalyzes H3 methylation. These bilingual "read-write" proteins form an interdependent positive feedback loop capable of transmitting sequence-independent silent information over multiple generations.