Immune-restricted epigenetic reader SP140 maintains macrophage identity and activation states critical to intestinal homeostasis [RNA-seq]

Introduction: SP140 is a bromodomain/plant homeo domain (PHD)-containing reader with immune-restricted expression, and single nucleotide polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unknown. Results: Individuals carrying CD-associated SNPs within SP140 had defective SP140 mRNA splicing, diminished SP140 protein, and severely suppressed innate immune signatures that stratified them from other CD patients. Conclusion: SP140 is a critical orchestrator of macrophage identity, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by suppressed innate immunity. Overall design: RNA-seq of 8 samples of peripheral blood derived mononuclear cells from CD patients having T/T or C/C genotype for rs6716753 SNP, with and without LPS treatment. 4 samples from healthy individuals with and without LPS treatment. RNA-seq of human macrophages (total 8 samples from 2 independent donors) stimulated with IFNg for 24h, and LPS (100ng/mL) for 4 hours: siRNA mediated knockdown of SP140 versus controls. RNA-seq of human macrophages (total 8 samples from 2 independent donors) stimulated with IFNg for 24h, and LPS (100ng/mL) for 4 hours for each condition: siRNA mediated knockdown of SP140 versus controls.