The Speckled Protein (SP) Family: Immunity’s Chromatin Readers

Chromatin ‘readers’ are central interpreters of the epigenome that facilitate cell-specific transcriptional programs and are therapeutic targets in cancer and inflammation. The Speckled Protein (SP) family of chromatin ‘readers’ in humans consists of SP100, SP110, SP140, and SP140L. SPs possess functional domains (SAND, PHD, bromodomain) that dock to DNA or post-translationally modified histones and a caspase activation and recruitment domain (CARD) to promote multimerization. Mutations within immune expressed SPs associate with numerous immunological diseases including Crohn’s disease, multiple sclerosis, chronic lymphocytic leukemia, veno-occlusive disease with immunodeficiency, as well as Mycobacterium tuberculosis infection, underscoring their importance in immune regulation. In this review, we posit that SPs are central chromatin regulators of gene silencing that establish immune cell identity and function. The speckled protein (SP) family of chromatin ‘readers’ in humans comprises SP100, SP110, SP140, and SP140L.The mouse SP family comprises Sp100, Sp110, and Sp140 and is only ~45% homologous to human SPs at the amino acid level, necessitating both mouse and human studies of SPs.SPs are highly expressed in innate and adaptive immune cells, with SP140 being immune restricted. SPs are also interferon (IFN)-stimulated genes (ISGs).Mutations in human SP140 associate with three immunological diseases: Crohn’s disease, chronic lymphocytic leukemia, and multiple sclerosis. Mutations in human SP110 associate with veno-occlusive disease with immunodeficiency (VODI). Mouse SPs can act as determinants of resistance to intracellular pathogen infections such as Mycobacterium tuberculosis.The SP family members possess a SAND domain, a plant homeodomain (PHD), and a caspase activation and recruitment domain (CARD) that share high homology with these domains found in autoimmune regulator (Aire); these domains suggest that SPs can bind to DNA directly, ‘read’ histone methylation status, and multimerize, respectively. In addition, SPs contain a bromodomain (BRD) that may read histone acetylation status.Human SPs localize to promyelocytic leukemia (PML) nuclear bodies (NBs) in human cell lines – dynamic nuclear protein aggregates interspersed between chromatin that can measure up to 2 μm in diameter. The presence of an intrinsically disordered region (IDR) exclusively in human SPs suggest that they may phase separate.By virtue of their localization to PML-NBs, SPs have