Molecular Mechanisms of Establishment and Inheritance of Epigenetic Transcriptional Memory in Saccharomyces cerevisiaePublic
For some inducible genes, the rate and molecular mechanism of transcriptional activation depend on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation, and requires both changes in chromatin structure and recruitment of poised RNA polymerase II (RNAPII) to the promoter. A well-established model for epigenetic transcriptional memory is the INO1 gene as induced by inositol starvation in Saccharomyces cerevisiae. It has been previously found that this state requires the binding of the transcription factor Sfl1, to the Memory Recruitment Sequence (MRS), an interaction with Nup100 at the Nuclear Pore Complex (NPC), deposition of H3K4me2 by a remodeled COMPASS complex, presence of SET3C binding to protect the histone marks, incorporation of H2A.Z by SWR1C, a memory-specific PIC that contains Ssn3, and a poised RNAPII. In my work, I have shown that establishment of this state involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). Additionally, while H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Furthermore, unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication. I also show that inositol starvation is not the only way to induce chromatin modifications associated with memory at the INO1 gene and that inducing the INO1 gene by different stresses can cause the formation of molecularly similar chromatin states that can last for varying lengths of time. Thus, my work adds significantly to the molecular understanding of both the establishment and maintenance of chromatin modifications associated with memory as well as showing that different stresses can lead to slightly different chromatin modifications all of which has broad implications for epigenetic transcriptional regulation in eukaryotes.