| Organisms respond to their environment through changes in transcription. In response to various conditions, some genes exhibit epigenetic transcriptional memory, through which the strength of their expression in response to a stimulus is enhanced by previous exposure to that stimulus. This phenomenon is observed from budding yeast to plants to humans. To understand the molecular basis for memory, I studied the yeast INO1 gene as a model. We previously knew that INO1 memory required a cis-acting DNA promoter element, a Memory Recruitment Sequence (MRS), and led to changes in chromatin structure of the promoter, including incorporation of histone H2A.Z and dimethylation of histone H3, lysine 4 (H3K4me2). These changes permit binding of poised, preinitiation RNA Polymerase II (RNAPII). I showed that the transcription factor Sfl1 binds to the MRS to initiate memory and is essential for all aspects of INO1 memory. I further showed that remodeling of the Set1/COMPASS methyltransferase during memory allows H3K4me2 in the gene promoter and that this mark recruits a reader complex (SET3C) that is essential for memory. Finally, I found that the CDK8 kinase module of Mediator is recruited specifically during memory and that this form of Mediator recruits RNAPII in a poised form to INO1, bypassing the rate-limiting step in future transcriptional activation. This mechanism is shown to other yeast and human genes. Thus, my work shows that transcriptional memory is regulated of both conditional binding by a transcription factor and repurposing chromatin remodelers used during transcription to create a novel, poised state that promotes future reactivation. This work has broad implications as to the mechanistic relationship between transcriptional regulation and adaptive epigenetic phenomena. |
