The chromatin reader SP140 regulates intestinal innate immune responses to microbes

Abstract

Abstract Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) within SP140 that associate with Crohn’s disease (CD) in addition to multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). SP140 is a transcriptional regulator expressed exclusively in immune cells. It is part of the Speckled Protein family that also contains SP100, SP110, and SP140L and shares high homology with autoimmune regulator (Aire). We have previously shown that SP140 is a critical orchestrator of macrophage identity by occupying and repressing silenced lineage-inappropriate genes. However, the role for SP140 functional domains in regulating macrophages identity and transcriptional responses to microbial sensing remained unknown. Here we show how SP140 influences innate immune responses to microbes. By engineering domain mutants, we investigate how the chromatin-binding domains (SAND, plant homeodomain, and bromodomain) and the caspase activation and recruitment domain (CARD) within SP140 dictate macrophage cytokine production. Furthermore, we determine how SP140 localization to promyelocytic leukemia (PML)-nuclear bodies affects function. Global deficiency of SP140 results in exacerbated colitis in mice, and a loss of SP140 specifically in the hematopoietic compartment results in microbial dysbiosis. Collectively, our work provides functional characterization of the novel chromatin regulator SP140 and how disease variants may contribute to immunological disease.