Published on Fri Jul 16 2021

BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis

Hoffner O'Connor, M., Berglind, A., Kennedy, M. M., Keith, B. P., Lynch, Z. J., Schaner, M. R., Steinbach, E. C., Herzog, J., Trad, O. K., Jeck, W. R., Arthur, J. C., Sartor, R. B., Furey, T., Sheikh, S. Z.

In colitis, macrophage functionality is altered compared to homeostatic conditions. 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, (+)-

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Abstract

Introduction: In colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and 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. Methods: We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or 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. Results: Treatment 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 the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice. Conclusion: We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.