Polycomb Responds to Low Levels of Transcription

Abstract

SUMMARY How is Polycomb (Pc), a eukaryotic negative regulator of transcription, targeted to specific mammalian genes? Our genome-wide analysis of the Pc mark H3K27me3 in murine cells that revealed Pc is preferentially associated with CpG island promoters of genes that are transcribed at a low level, and less so with promoters of genes that are either silent or more highly expressed. Studies of the CpG island promoter of the Kit gene demonstrate that Pc is largely absent when the gene is silent in myeloid cells as well as when the gene is highly expressed in mast cells. Manipulations that increase transcription in the former case, and reduce it in the latter, increase Pc occupancy. The average negative effect of Pc, we infer, is about two-fold. We suggest possible biological roles for such negative effects and propose a mechanism by which Pc might be recruited to weakly transcribed genes.

Promoter CpG density predicts downstream gene loss-of-function intolerance

“…Since a comprehensive assessment of this is currently out of reach (due to the lack of extensive genome-wide binding data for most regulatory factors), we focused on EZH2 as a proof-ofprinciple. EZH2 is a relatively well-characterized histone methylstransferase that specifically localizes to CpG islands of non-transcribed genes (Figure 3a, Supplemental Figure S8; Riising et al (2014) and Berrozpe et al (2017)). We discovered that tissue-specific genes with CpGdense and EZH2-bound promoters (EZH2 binding in at least 2 ENCODE experiments) have lower LOEUF compared to their EZH2-unbound counterparts (Figure 3b; regression β = −5.66, p = 5.21 · 10 −8 , for the interaction between CpG density and EZH2 binding, conditional on tissue specificity τ > 0.6).…”

The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation

“…In hyperacetylated chromatin, TF-binding motifs previously cryptic in heterochromatin become exposed and can trap TFs, reducing their free concentration and consequently their availability for binding to enhancers (Model formalized in the S.I.). Then, E-H3K27 methylases like polycomb could complete the system by methylating poorly occupied E-H3K27, as verified in [59], thus precluding their reacetylation.…”

“…They are strongly upregulated in the TSA treatment by 22-and 19-fold for SNAI1 and SNAI2 respectively, and in cancer, such as during the mammary hormonal escape, where the SNAI repress ERα and E-cadherin [61]. Another excellent molecular candidate for repressing differentiation genes after chromatin opening is the polycomb system mentioned above, which could simply validate the lower occupancy of enhancers by TFs [59] (model in the S.I.) and proceed to their closure.…”

“…by absence of expression than by active repression. Repressive machineries like polycomb complexes, which suppress the expression of many genes in embryonic stem cells [25], could only ratify preexisting low transcription states, as suggested in [59], thereby locking selectively the genes which have already lost their Waddington-type fight in antagonistic genetic circuits. The relative contributions of basal vs regulated expression (b/a) are the main regulator of the balance of cellular dedifferentiation/differentiation in the present model.…”

The synthetic histone-binding regulator protein PcTF activates interferon genes in breast cancer cells

“…However, a recent study using genome-wide ChIP-seq and transcription profiles in murine cells showed that H3K27me3 was enriched at genes with low levels of expression and depleted at completely silenced genes, and highly expressed genes [78] . We were prompted to investigate whether the chromatin features at PcTF-activated genes might reflect a low to moderate expression state.…”