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 been implicated in transcriptional repression of host or viral genomes. The function of SP140 was recently elucidated showing that it occupies heterochromatin and represses lineage-inappropriate genes such as HOX to maintain macrophage identity in mice and humans.
SARS-CoV-2 has mutually illuminated our collective knowledge and knowledge gaps, particularly in antiviral defense and therapeutic strategies. A recent study in Science (Poirier et al., 2021) ...uncovers an ancient antiviral mechanism that mammals utilize to suppress viruses, including SARS-CoV-2 and Zika virus, that could have broad implications for therapeutic strategies.
SARS-CoV-2 has mutually illuminated our collective knowledge and knowledge gaps, particularly in antiviral defense and therapeutic strategies. A recent study in Science (Poirier et al., 2021) uncovers an ancient antiviral mechanism that mammals utilize to suppress viruses, including SARS-CoV-2 and Zika virus, and that could have broad implications for therapeutic strategies.
DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using ...the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
•Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design•KORD is selectively activated by salvinorin B, and not by endogenous opioids•KORD robustly silenced multiple neuronal subtypes•Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control
The κ-opioid receptor (KOR) was used as a template to generate a novel inhibitory DREADD (KORD), which is activated by salvinorin B and insensitive to endogenous opioid peptides. Sequential activation of the inhibitory KOR-DREADD and an excitatory M3-DREADD facilitated the bidirectional, multiplexed modulation of behavior.
•Epigenetics is a therapeutically tractable mechanism linking genetics and environmental cues in IBD.•Variants of human epigenetic regulators or regulatory regions associate with IBD ...susceptibility.•Individual epigenetic enzymes exacerbate or protect mouse models of colitis.•Intestinal bacteria modulate DNA, histone modifications and chromatin accessibility.•Cellular and bacteria-derived metabolites are major determinants of epigenetic enzyme function.
Environmental triggers in the context of genetic susceptibility drive phenotypes of complex immune disorders such as Inflammatory bowel disease (IBD). One such trigger of IBD is perturbations in enteric commensal bacteria, fungi or viruses that shape both immune and neuronal state. The epigenome acts as an interface between microbiota and context-specific gene expression and is thus emerging as a third key contributor to IBD. Here we review evidence that the host epigenome plays a significant role in orchestrating the bidirectional crosstalk between mammals and their commensal microorganisms. We discuss disruption of chromatin regulatory regions and epigenetic enzyme mutants as a causative factor in IBD patients and mouse models of intestinal inflammation and consider the possible translation of this knowledge. Furthermore, we present emerging insights into the intricate connection between the microbiome and epigenetic enzyme activity via host or bacterial metabolites and how these interactions fine-tune the microorganism-host relationship.
•Chromatin dynamics regulate pattern, timing and magnitude of gene expression.•Signal transduction downstream of TLR4 regulate histones for inducible gene transcription.•Metabolic shifts and ...epigenetics of innate immune cells are intimately linked.•Chromatin dynamics enable memory of microbial exposure for tolerance or trained immunity.•Epigenetic therapies demonstrate promise for inflammatory disease.
A hallmark of the innate immune system is its ability to rapidly initiate short-lived or sustained transcriptional programs in a cell-specific and pathogen-specific manner that is dependent on dynamic chromatin states. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental cues also induce changes in chromatin that can either promote tolerance or 'train' innate immune cells for amplified secondary responses. We review chromatin processes that enable innate immune cell differentiation and functional transcriptional responses in naive or experienced cells, in concert with signal transduction and cellular metabolic shifts. We discuss how immune chromatin mechanisms are maladapted in disease and novel therapeutic approaches for cellular reprogramming.
Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are ...still characterizing what constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation. Illuminating this will represent a first step toward developing virome-focused therapies.
Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Speckled Protein 140 (SP140) is an immune-restricted chromatin “reader” that ...is associated with Crohn’s disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the disease-causing mechanisms of SP140 remain undefined. Here, we identify an immune-intrinsic role for SP140 in regulating phagocytic defense responses to prevent the expansion of inflammatory bacteria. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis that was transmissible upon cohousing and ameliorated with antibiotics. Loss of SP140 results in blooms of Proteobacteria, including Helicobacter in Sp140−/− mice and Enterobacteriaceae in humans bearing the CD-associated SP140 loss-of-function variant. Phagocytes from patients with the SP140 loss-of-function variant and Sp140−/− mice exhibited altered antimicrobial defense programs required for control of pathobionts. Thus, mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by microbiota.
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•Epigenetic reader SP140 facilitates antibacterial programs in macrophages•Exacerbated colitis in Sp140-deficient mice is dependent on microbiota dysbiosis•Pro-inflammatory Proteobacteria expand in SP140-deficient mice and humans
A loss-of-function mutation in the chromatin reader SP140 is associated with Crohn’s disease. Fraschilla et al. demonstrate that SP140-deficient phagocytes lack the ability to mount homeostatic antibacterial responses, and expansion of pathobionts occurs in the intestine of mice and humans that lack SP140.
The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body's first line of defense against infection. Although signaling pathways and transcription ...factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary cell lineage as well as context‐specific gene expression in diverse innate immune cell types. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental triggers also induce changes in histone modifications that can either promote tolerance or ‘train’ innate immune cells for a more robust antigen‐independent secondary response. Here we review the important contribution of epigenetic factors to the initiation, maintenance and training of innate immune responses. In addition, we explore how pathogens have hijacked these mechanisms for their benefit and the potential of small molecules targeting chromatin machinery as a way to boost or subdue the innate immune response in disease.
The March 2015 issue contains a Special Feature on the epigenetic mechanisms underlying health and disease. Epigenetic modifications to chromatin influence the transcriptional status of our genes. Thus, understanding the epigenetic mechanisms that regulate immune cell fate are of great importance as they will provide insight into not only how to boost immune responses but also alter harmful ones such as autoimmunity and cancer. Immunology and Cell Biology thanks the coordinators of this Special Feature ‐ Rhys Allan ‐ for his planning and input.
Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and ...hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.
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