Transcription and chromatin-based surveillance mechanism controls suppression of cryptic antisense transcription

Abstract

Phosphorylation of the RNA polymerase II C-terminal domain Y 1 S 2 P 3 T 4 S 5 P 6 S 7 consensus sequence coordinates key events during transcription, and its deregulation leads to defects in transcription and RNA processing. Here, we report that the histone deacetylase activity of the fission yeast Hos2/Set3 complex plays an important role in suppressing cryptic initiation of antisense transcription when RNA polymerase II phosphorylation is dysregulated due to the loss of Ssu72 phosphatase. Interestingly, although single Hos2 and Set3 mutants have little effect, loss of Hos2 or Set3 combined with ssu72D results in a synergistic increase in antisense transcription globally and correlates with elevated sensitivity to genotoxic agents. We demonstrate a key role for the Ssu72/Hos2/Set3 mechanism in the suppression of cryptic antisense transcription at the 3 0 end of convergent genes that are most susceptible to these defects, ensuring the fidelity of gene expression within dense genomes of simple eukaryotes.

Repression of pervasive antisense transcription is the primary role of fission yeast RNA polymerase II CTD serine 2 phosphorylation

“…Our findings unveil a critical role for CTD S2 phosphorylation in the establishment of a repressive chromatin state that prevents cryptic transcription. While the accumulation of antisense transcription was previously noted using a similar CTD S2A mutant ( 102 ), the underlying mechanism had not been determined. We now show that CTD S2 phosphorylation is required for the activation of the Set2-Clr6(II) axis, which maintains the coding regions of genes in a hypoacetylated state and thereby represses initiation from cryptic intragenic promoters.…”

Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis

“…The function of HDACs on active genomic regions has been elucidated in several contexts. In yeast, cotranscriptional methylation (H3K36me3 and H3K4me2) recruits HDAC containing complexes (Rpd3S and Set3C) to suppress intragenic transcription and delay induction of genes that overlap non-coding RNAs ( Carrozza et al, 2005 ; Keogh et al, 2005 ; Li et al, 2007 ; Kim and Buratowski, 2009 ; Kim et al, 2012 ; Heo et al, 2021 ). Genetic deletion of Set3C affects transcript levels only in altered growth conditions ( Lenstra et al, 2011 ), consistent with the notion that cyclical histone acetylation acts as a mechanism to regulate dynamics and fidelity of transcription.…”

Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis

“…The function of HDACs on active genomic regions has been elucidated in several contexts. In yeast, cotranscriptional methylation (H3K36me3, H3K4me2) recruits HDAC containing complexes (Rpd3S, Set3C) to suppress intragenic transcription and delay induction of genes that overlap non-coding RNAs (Carrozza et al, 2005; Keogh et al, 2005; Li et al, 2007; Kim and Buratowski, 2009; Kim et al, 2012; Heo at al., 2021). Genetic deletion of Set3C affects transcript levels only in altered growth conditions (Lenstra et al, 2011), consistent with the notion that cyclical histone acetylation act as a mechanism to regulate dynamics of RNA induction and fidelity of transcription.…”