Abstract
Targeting epigenetic reader proteins by small molecule inhibitors represents a new therapeutic concept in autoimmune diseases such as rheumatoid arthritis (RA). Although inhibitors targeting bromodomain protein 1 (BRD1) are in development, the function of BRD1 has hardly been studied. We investigated the therapeutic potential of BRD1 inhibition in joint-resident cells in RA, synovial fibroblasts (SF) and macrophages. The proliferation of SF was decreased upon BRD1 silencing, accompanied by the downregulation of genes involved in cell cycle regulation. Silencing of BRD1 in SF decreased the basal expression of MMP1 but increased TNF-α- and LPS-induced levels of MMP3, IL6 and IL8. In monocyte-derived macrophages (MDM), silencing of BRD1 decreased the LPS-induced expression of TNF-α, but did not significantly affect basal and the TNF-α- and LPS-induced expression of IL6 and IL8. Our data point to a cell type- and a stimulus-specific function of BRD1. Inhibiting BRD1 could have potential beneficial effects in RA via decreasing the proliferation of SF. Anti-inflammatory effects were limited and only observed in MDM.
Highlights
Histone lysine acetylation, in combination with other post-translational modifications and DNA methylation determines the epigenetic code that regulates gene expression
Inhibitors targeting the bromodomain of bromodomain protein 1 (BRD1) (BRPF2) have recently been developed[6,7] but there is a lack of knowledge on the functional role of BRD1 in adult tissues
We assessed the role of BRD1 in joint resident cells, synovial fibroblasts (SF) and macrophages which both contribute to hyperplasia of the synovium and promotion of inflammation found in RA14
Summary
In combination with other post-translational modifications and DNA methylation determines the epigenetic code that regulates gene expression. Enzymes that read and erase histone acetylation marks are involved in regulating pathogenic pathways in rheumatoid arthritis (RA), including inflammation[1]. Bromodomain proteins (BRD) are epigenetic readers of acetylated histones. Targeting BRDs by small-molecule inhibitors has emerged as a new potential therapy in inflammation and arthritis[2]. Inhibitors against the family of bromodomain and extra-terminal (BET) proteins exhibit anti-inflammatory properties[3] and show beneficial effects in RA synovial fibroblasts (RASF)[4] and experimental arthritis[5]. First inhibitors targeting members of a distinct BRD family, the bromodomain and plant homeodomain finger-containing (BRPF) family, including BRPF1, BRD1 (BRPF2), and BRPF3 have recently been developed[6,7], they have not been tested regarding their anti-inflammatory potential. We evaluated the function of BRD1 in joint resident cells, synovial fibroblasts (SF) and macrophages, and explored the potential of BRD1 inhibition as a treatment strategy in RA
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