p65-activated Histone Acetyltransferase Activity Is Repressed by Glucocorticoids

Abstract

Glucocorticoids acting through their specific receptor can either enhance or repress gene transcription. Dexamethasone represses interleukin-1␤-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associated histone acetyltransferase (HAT) activity and by recruiting histone deacetylase 2 (HDAC2) to the p65-HAT complex. Here we show that mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene expression but represses interleukin-1␤-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor release by 50% maximally. Mifepristone was able to inhibit p65-associated HAT activity to the same extent as dexamethasone but failed to inhibit the natural promoter to an equal extent due to an inability to recruit HDAC2 to the p65-associated HAT complex. These data suggest that the maximal repressive actions of glucocorticoids require recruitment of HDAC2 to a p65-HAT complex. These data also suggest that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.

How Do Corticosteroids Work in Asthma?

“…The activation of genes by corticosteroids is associated with a selective acetylation of lysine residues 5 and 16 on histone-4, resulting in increased gene transcription (9,22) (Figure 4). Activated glucocorticoid receptors may bind to coactivator molecules, such as CBP or PCAF, as well as steroid-receptor coactivator-1, which itself has HAT activity (23,24).…”

“…This speculation has led to a search for novel corticosteroids that selectively transrepress without significant transactivation, thus reducing the potential risk for systemic side effects. Because corticosteroids bind to the same glucocorticoid receptors, this seems at first to be an unlikely possibility, but while DNA binding involved a glucocorticoid receptor homodimer, interaction with transcription factors AP-1 and NF-B and coactivators involves only a single glucocorticoid receptor (22). A separation of transactivation and transrepression has been demonstrated by using reporter gene constructs in transfected (see Glossary) cells using selective mutations of the glucocorticoid receptor (71).…”

Corticosteroid effects on cell signalling

“…This has led to a search for novel corticosteroids that selectively trans-repress without significant trans-activation or cis-repression, thus reducing the potential risk of systemic side-effects. Since corticosteroids bind to the same GR, this seems at first to be an unlikely possibility, but, although DNA binding involves a GR homodimer, interaction with transcription factors AP-1 and NF-kB and coactivators involves only a single GR [28]. A separation of trans-activation and trans-repression has been demonstrated using reporter gene constructs with selective mutations of the GR in transfected cells [103].…”

“…2) [14,28]. Activated GRs may bind to coactivator molecules, such as CBP and pCAF, as well as steroid receptor coactivator (SRC)-1 and glucocorticoid receptor-interacting protein 1 (GRIP1 or SRC-2), which all possess HAT activity [29,30].…”

Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index

“…Behind the transrepression activity, several mechanisms are hidden. For example, the role of cofactors and histone deacetylases for example is still under discussion although much research has been done in the past (Ito et al, 2000;Ito et al, 2001;Vanden Berghe et al, 2002). Furthermore, there are also transactivation events induced by GCs that are therapeutically beneficial, as has been shown for example for MKP-1 (Kassel et al, 2001, Clark, 2003, lipocortin-1 (Calandra et al, 1995) or very recently for glucocorticoid-induced leucin zipper (GILZ) (Hamdi, et al, 2007).…”