BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis

Abstract

IntroductionIn colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice.MethodsWe performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization.ResultsTreatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice.ConclusionWe identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.

Selective BET inhibitor RVX‐208 ameliorates periodontal inflammation and bone loss

“…For example, the treatment of JQ1 inhibited the inflammatory gene transcription associated with LPS stimulation and prevented LPS‐induced sepsis (Belkina et al, 2013; Nicodeme et al, 2010). Hoffner O'Connor et al (2022) showed that JQ1 suppressed LPS‐induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP‐1 and IRF transcription factors, and attenuated the onset of microbiota‐induced colitis. In inflammatory bone disease, both JQ1 and I‐BET 151 are pan‐bromodomain inhibitors, and can prevent pathological bone resorption in experimental arthritis (Park‐Min et al, 2014), oestrogen‐related osteoporosis (Baud'huin et al, 2017; Park‐Min et al, 2014) and alveolar bone loss (Meng et al, 2014).…”

“…In haematoxylin and eosin staining (Figure6c), compared with DMSO group, RVX-208 treatment appeared to result in less epithelium hyperplasia and less immune cell infiltration.4 | DISCUSSIONIn recent years, BET inhibitors have emerged as promising candidates for treating inflammatory diseases. For example, the treatment of JQ1 inhibited the inflammatory gene transcription associated with LPS stimulation and prevented LPS-induced sepsis(Belkina et al, 2013;Nicodeme et al, 2010) Hoffner O'Connor et al (2022). showed that JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions U R E 3 RVX-208 inhibited osteoclast differentiation.…”

Inhibitor of bromodomain and extraterminal domain proteins decreases transcription of Cd33 in the brain of mice subjected to systemic inflammation; a promising strategy for neuroprotection

“…Because inhibitors of BET proteins were demonstrated to efficiently attenuate several LPS-evoked changes [2,32], the second goal of this study was to analyse the impact of JQ1, an inhibitor of BET proteins, on LPS-changed expression of AD-GRF genes in the hippocampus during systemic inflammation. In mice, JQ1 is well tolerated even after chronic treatment, and it efficiently enters the brain (AUC brain /AUC plasma = 98%) [43,45,48].…”

Histone acetylation, BET proteins, and periodontal inflammation

“…This emerges as a potent approach to inhibit inflammation cascades because it prevents the transcription initiation of inflammatory genes. Nicodeme et al (2010) successfully synthesized a compound (GSK525762A, IBET762) that mimicked acetylated histones and disrupted chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, while also conferring protection against LPS-induced endotoxic shock and bacteria-induced JQ1, a well-studied pan-BET inhibitor, suppressed the activation of a specific subset of LPS-inducible genes that encode cytokines, chemokines, and transcription factors involved in inflammatory response (Belkina et al, 2013;Hoffner O'Connor et al, 2022). The presence of JQ1 disassociates BET proteins from the promoters and super-enhancers of pro-inflammatory genes (Belkina et al, 2013;Hoffner O'Connor et al, 2022;Krishna et al, 2021).…”