Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression

Abstract

The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.

Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function

“…As shown in Additional file 8 Fig. S8, the features of neutrophil extracellular traps (NETs) include: (i) a defense mechanism against both micro-organisms and sterile triggers, (ii) a DNA scaffold with granule-derived proteins, such as proteases (e.g., elastase) or citrullinated histone H3, (iii) an important role in inflammation, autoimmunity and other pathophysiological conditions (either detrimental or beneficial), and/or (iv) it can be prompted by many triggers and via multiple distinct pathways with often unknown interrelationship [ 54 – 57 ]. The NET pathways shown in Fig.…”

“…Heatmaps representing the profiling of the neutrophil phenotype (based on a manually curated set of markers taken from specific literature reports) are presented in Fig. 3 B [ 54 – 57 ]. The heatmaps show the hierarchical clustering of these markers in healthy control subjects and in COVID-19 patients along with their predicted inter-dependence (Pearson correlation algorithm; Fig.…”

Acetylation-induced proteasomal degradation of the activated glucocorticoid receptor limits hormonal signaling

“… 43 Moreover, p300 sequestration at GR binding sites in activated and repressed gene loci suggests that p300-dependent GR acetylation may not only be associated with transactivation but also with transrepression. 44 Although antagonists such as RU486 drive nuclear translocation of GR, the recruitment of corepressors, such as histone deacetylases, instead of coactivators such as p300/CBP, results in antagonist activity. 45 Co-treatment with deacetylase inhibitors did not rescue RU486-dependent repression of acK154 indicating an interference in the interaction between antagonist-bound GR and p300/CBP ( Figure 3 F).…”

Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer

“…However, indirect processes have recently gained more prominence, including such mechanisms as coregulator squelching and TF cascades. In the former, the activation of a TF, such as AR or GR, can sequester coregulators from active enhancers to their binding sites indirectly repressing the pre-existing enhancers (59, 60). In the latter, the activation or repression of initial TF leads to a cascade where the production of another TF is increased, resulting indirectly in the activation of new pathways through the produced TF (61).…”