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• W3120583721 abstract "The hypothesis titled “Soft repression: subtle transcriptional regulation with global impact,”[1] introduces a novel perspective to our understanding of the function and impact of repressor complexes. According to Mitra, Raicu, and colleagues, specific transcriptional repressors provide a level of “soft repression,” in addition to their known ability to switch off gene expression. Such repression lightly modulates the levels of target transcripts instead of outright silencing them. This modulatory ability is difficult to observe by traditional methods, where arbitrary cut-off thresholds often exclude the fold changes resulting from “soft repression.” Nonetheless, this repression is likely to engage important cellular functions, as evidenced by numerous loss-of-function studies. This novel hypothesis allows us to reconcile the nominal changes in the transcriptome upon modulation of corepressor expression with the phenotypes observed. To support their hypothesis, the authors analyze genome-wide data obtained from two well-known repressor complexes, the retinoblastoma (Rb) complex and the histone deacetylase-associated Sin3 complex. These complexes drive a well-established strong repression of their targets. However, further analysis of ChIP-seq and RNA-seq data reveal that both complexes also directly fine-tune the expression of genes that are generally active (housekeeping genes). These findings hint to unsuspected regulatory roles in homeostasis for these repressor complexes. So far, the mild transcriptional regulation of housekeeping genes by the Rb or the Sin3 complex has been mostly overlooked or dismissed as off-target effects. Expression profile analysis of these housekeeping genes points to significant yet understudied roles in development. The authors propose that these corepressor complexes fine-tune the expression of these genes throughout development. In doing so, they contribute to an essential transcriptional control for proper development. Finally, this study explores the potential mechanisms by which soft repression could function. Transcriptional silencing is widely driven by chromatin and epigenetic changes affecting enhancers. However, the authors show that the Rb and Sin3 complexes are tethered to the promoter regions of the genes they “softly” repress. Binding to the promoter instead of the enhancer may incompletely hinder assembly of the transcription complex or transcription initiation, resulting in a weaker form of repression. Additionally, promoter binding could disrupt some of the transcriptional activation signals, providing a small but physiologically relevant deviation in the expression levels of an otherwise constitutively active gene. Further exploration is needed to better define the molecular bases for the differential impact of these complexes on the target genes they either silence or “softly repress.” For example, the Sin3 complex associates with different modules with specific chromatin-modifying activities.[2] Could a discrete Sin3 complex arrangement underline its function in soft repression, while an alternative one directs silencing? Another question lies in the biological impact of these slight modulations of repression. A moderate decrease in expression levels affecting several loci simultaneously is reminiscent of the mode of action of miRNAs, whose biological impact is not contested.[3] Similarly, slight changes in expression levels as a result of soft repression may affect the stochasticity of essential complexes, resulting in dramatic biological outcomes.[4] Finally, can additional repressor complexes employ this type of repression? While Sin3 and Rb provide the most evidence for functioning as soft repressors, the authors do not exclude other repressors from having the capacity to softly repress a subset of their target genes. Testing the ability of a complex to engage soft repression is not without its challenges, as detailed here. However, with the ongoing development of techniques to determine precise transcription levels, this fresh take on repression is likely to open novel avenues in our understanding of the biological function of well-studied repressive protein complexes. The authors declare no conflict of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study." @default.
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• W3120583721 date "2021-01-06" @default.
• W3120583721 modified "2023-09-27" @default.
• W3120583721 title "Softly but surely: A new perspective on transcriptional repression" @default.
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• W3120583721 doi "https://doi.org/10.1002/bies.202000326" @default.
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