Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 2 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001006186	Transcriptomic (N = 18) and epigenomic (N = 6) characterization of macrophages using RNA-sequencing and ChIP-sequencing (bait = SP140) in the presence of absence of SP140 inhibition.	Illumina HiSeq 2500 Illumina HiSeq 4000	30

Publications	Citations
Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140. Ghiboub M, Koster J, Craggs PD, Li Yim AYF, Shillings A, Hutchinson S, Bingham RP, Gatfield K, Hageman IL, Yao G, O'Keefe HP, Coffin A, Patel A, Sloan LA, Mitchell DJ, Hayhow TG, Lunven L, Watson RJ, Blunt CE, Harrison LA, Bruton G, Kumar U, Hamer N, Spaull JR, Zwijnenburg DA, Welting O, Hakvoort TBM, Te Velde AA, van Limbergen J, Henneman P, Prinjha RK, de Winther MPJ, Harker NR, Tough DF, de Jonge WJ. BMC Biol 20: 2022 182	11
The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential. Ghiboub M, Bell M, Sinkeviciute D, Prinjha RK, de Winther MPJ, Harker NR, Tough DF, de Jonge WJ. Curr Issues Mol Biol 45: 2023 4228-4245	1

Publications

Citations

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.
Ghiboub M, Koster J, Craggs PD, Li Yim AYF, Shillings A, Hutchinson S, Bingham RP, Gatfield K, Hageman IL, Yao G, O'Keefe HP, Coffin A, Patel A, Sloan LA, Mitchell DJ, Hayhow TG, Lunven L, Watson RJ, Blunt CE, Harrison LA, Bruton G, Kumar U, Hamer N, Spaull JR, Zwijnenburg DA, Welting O, Hakvoort TBM, Te Velde AA, van Limbergen J, Henneman P, Prinjha RK, de Winther MPJ, Harker NR, Tough DF, de Jonge WJ. BMC Biol 20: 2022 182

The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential.
Ghiboub M, Bell M, Sinkeviciute D, Prinjha RK, de Winther MPJ, Harker NR, Tough DF, de Jonge WJ. Curr Issues Mol Biol 45: 2023 4228-4245