Soft repression: Subtle transcriptional regulation with global impact

Abstract

Pleiotropically acting eukaryotic corepressors such as retinoblastoma and SIN3 have been found to physically interact with many widely expressed "housekeeping" genes. Evidence suggests that their roles at these loci are not to provide binary on/off switches, as is observed at many highly cell-type specific genes, but rather to serve as governors, directly modulating expression within certain bounds, while not shutting down gene expression. This sort of regulation is challenging to study, as the differential expression levels can be small. We hypothesize that depending on context, corepressors mediate "soft repression," attenuating expression in a less dramatic but physiologically appropriate manner. Emerging data indicate that such regulation is a pervasive characteristic of most eukaryotic systems, and may reflect the mechanistic differences between repressor action at promoter and enhancer locations. Soft repression may represent an essential component of the cybernetic systems underlying metabolic adaptations, enabling modest but critical adjustments on a continual basis.

Keywords: SIN3; gene regulation; metabolism; promoter; repression; retinoblastoma; transcription.

FIGURE 1

Comparison of hard versus soft repression. (A) Rb can function as a potent repressor on certain genes such as the cell cycle-related PCNA by blocking the E2F transactivation domain and inducing a repressed chromatin state. (B) In contrast, on other genes such as InR, Rb functions in concert with other factors that may have to balance each other’s activities, leading to more moderate repression of the gene

FIGURE 2

Conserved, direct targets of SIN3 and Rb exhibit soft, but significant repression. (A) SIN3 and Rb bind to a substantial number of the same genes in both the fly and mammalian systems, which indicates conservation of genome-wide binding by these corepressors. To determine this, we used the BioMart data mining tool and analyzed the intersection of fly and mammalian ChIP-seq datasets.^[55] Mouse genes for which orthologs can be identified in the fly were overlapped with fly genes bound by SIN3. Similarly, human genes for which orthologs can be identified in the fly were overlapped with fly genes bound by Rb. (B) Chart indicates GO categories misregulated after overexpression or knockdown of SIN3 or Rb in fly and mammalian systems. (C) Pie charts indicate the log₂-fold change of direct, repressed genes after Rb or SIN3 manipulations in worm, fly, and mammalian models. Totals listed are the number of genes misregulated for each organism and corepressor. Data obtained from^{[,–,,,Mouawad et al. in prep]}

FIGURE 3

Contrasting models for transcriptional repression: enhancer based hard repression (A, B) and promoter based soft repression (C, D). (A) At enhancers, activators and repressors work in a binary fashion, turning gene expression on and off in response to availability of binding sites and interaction with distal gene promoters. When an activator binds an available enhancer, it can turn on gene expression through chromatin looping. (B) If an enhancer is occluded through nucleosome remodeling and chromatin compaction, activator access is inhibited and the gene is turned off. (C) At promoters, soft repressors can fine-tune expression from the proximity to the transcriptional start site, sometimes through interaction with transcription factors (TF) bound to DNA. There is an interplay between activators and repressors, which compete for DNA recruitment to impact the chromatin environment and modulate gene expression. On the left, a promoter proximal TF interacts with cofactors such as histone acetyltransferases (HAT) to turn on expression of gene X, while on the right, (D) the soft repressor complex, which many times includes a histone deacetylase (HDAC) in the case of Rb and SIN3, is more potent than the activator. The complex deacetylates nearby histone tails and dials down expression of gene X, but does not completely turn it off.