RSC primes the quiescent genome for hypertranscription upon cell-cycle re-entry

Abstract

Quiescence is a reversible G0 state essential for differentiation, regeneration, stem cell renewal, and immune cell activation. Necessary for long-term survival, quiescent chromatin is compact, hypoacetylated, and transcriptionally inactive. How transcription activates upon cell-cycle re-entry is undefined. Here we report robust, widespread transcription within the first minutes of quiescence exit. During quiescence, the chromatin-remodeling enzyme RSC was already bound to the genes induced upon quiescence exit. RSC depletion caused severe quiescence exit defects: a global decrease in RNA polymerase II (Pol II) loading, Pol II accumulation at transcription start sites, initiation from ectopic upstream loci, and aberrant antisense transcription. These phenomena were due to a combination of highly robust Pol II transcription and severe chromatin defects in the promoter regions and gene bodies. Together, these results uncovered multiple mechanisms by which RSC facilitates initiation and maintenance of large-scale, rapid gene expression despite a globally repressive chromatin state.

RSC and GRFs confer promoter directionality by limiting divergent noncoding transcription

“…For example, RSC represses antisense transcription from the 3' ends of gene bodies, which is spatially distinct from the divergent noncoding transcription events which we report here (Alcid & Tsukiyama 2014, Cucinotta et al 2021. In addition, RSC-mediated positioning of the +1 nucleosome can affect TSS selection, resulting in increased transcription initiation in the sense direction within promoters (Cucinotta et al 2021, Klein-Brill et al 2019, Kubik et al 2019. This work demonstrates that RSC is important for repressing divergent noncoding transcription upstream in coding gene promoters, and this is important for controlling the directionality of promoters.…”

“…RSC-mediated nucleosome positioning also functions in suppressing other aberrant transcription events. For example, RSC represses antisense transcription from the 3' ends of gene bodies, which is spatially distinct from the divergent noncoding transcription events which we report here (Alcid & Tsukiyama 2014, Cucinotta et al 2021. In addition, RSC-mediated positioning of the +1 nucleosome can affect TSS selection, resulting in increased transcription initiation in the sense direction within promoters (Cucinotta et al 2021, Klein-Brill et al 2019, Kubik et al 2019.…”

“…Specifically, RSC positions the +1 nucleosome in gene promoters to allow pre-initiation complex (PIC) assembly and transcription start site (TSS) scanning (Klein-Brill et al 2019). RSC limits aberrant transcription from upstream in promoters in the sense direction, but also limits transcription initiating from the 3’ end of gene bodies in the antisense direction (Alcid & Tsukiyama 2014, Cucinotta et al 2021, Klein-Brill et al 2019, Kubik et al 2019). The role of RSC in controlling promoter directionality remains an area of interest.…”

Genomic Occupancy of the Bromodomain Protein Bdf3 Is Dynamic during Differentiation of African Trypanosomes from Bloodstream to Procyclic Forms

“…In other systems, quiescence results in a global decrease in acetylation levels ( 58 – 60 ). Specific chromatin remodeling enzymes are required to generate hypertranscription necessary for exiting the quiescent state ( 61 ). If an increase in acetylation levels and increased transcription are necessary during the transition from the quiescent stumpy form to the cycling procyclic form, this could result in the observed increase in Bdf3 occupancy following the differentiation cue.…”

Quiescence Through the Prism of Evolution

“…Besides, in S. cerevisiae, the polymerase II is poised onto promoter of genes that are critical for proliferation resumption (Radonjic et al, 2005). In parallel, the chromatin remodeling complex (RSC) is bound to genes induced upon quiescence exit and facilitates rapid gene expression firing, despite a globally repressive chromatin state maintained compacted by histone specific modifications (McKnight et al, 2015;Swygert et al, 2019;Cucinotta et al, 2021). Hence, unicellular quiescent cells seem to be prepared to respond rapidly to favorable conditions and mechanisms accompanying quiescence establishment may be an asset for the competition within a given environment.…”