Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory

Abstract

For some inducible genes, the rate and molecular mechanism of transcriptional activation depends 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. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. 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.

STAT1 is required to establish but not maintain IFNγ-induced transcriptional memory

“…Furthermore, these results suggest that while RNA polymerase II has been detected on promoters of primed HLA genes (Light et al 2013), it may itself not be the primary driver of transcriptional memory. In line with this, recent elegant experiments in yeast have shown that in the case of INO1 transcriptional memory, RNA polymerase II is poised but not required for memory (Sump et al 2022).…”

Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition

“…In budding yeast, INO1 transcriptional memory induced by previous inositol starvation primes the rapid reactivation of INO1 upon exposure to the second stimulus ( D'Urso and Brickner, 2017 ). INO1 is required for the conversion of glucose to myoinositol in phospholipid biosynthesis ( Graves and Henry, 2000 ; Sump et al, 2022 ). The detailed molecular mechanism of INO1 memory is under investigation, and the current model of INO1 memory is summarized in a recent study ( Sump et al, 2022 ).…”

“…INO1 is required for the conversion of glucose to myoinositol in phospholipid biosynthesis ( Graves and Henry, 2000 ; Sump et al, 2022 ). The detailed molecular mechanism of INO1 memory is under investigation, and the current model of INO1 memory is summarized in a recent study ( Sump et al, 2022 ). Briefly, INO1 memory requires a TF-dependent interaction with the nuclear pore complex (NPC), alterations in chromatin structure, and recruitment of “poised” Pol II to the promoter.…”

“…On initial activation, INO1 repositions from the nucleoplasm to the nuclear periphery and interacts with the NPC ( Sumner et al, 2021 ; Sump et al, 2022 ). During subsequent repression, INO1 continues to interact with NPC, which requires the transcription factor Sfl1, the memory recruitment sequences (MRS) in the promoter, to which Sfl1 specifically binds, and the nuclear pore protein Nup100 ( Light and Brickner, 2013 ; D'Urso et al, 2016 ; Sump et al, 2022 ).…”

“…Recently repressed INO1 acquires the essential histone mark H3K4me2 within its promoter domain ( D'Urso and Brickner, 2017 ). Similarly, H2A.Z is incorporated upstream of the TSS during INO1 memory ( Brickner et al, 2007 ; Sump et al, 2022 ). Active gene promoters generally possess high levels of histone acetylation, H3K4me3, and H3K4me2; H3K4 methylation is catalyzed by the SET1/COMPASS complex, which is the sole methyltransferase of H3K4 in yeast ( Shilatifard, 2012 ; D'Urso and Brickner, 2017 ; Chen et al, 2018 ).…”