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Control of type I interferon production is crucial to combat infection while preventing deleterious inflammatory responses, but the extent of the contribution of post-transcriptional mechanisms to innate immune regulation is unclear. Here, we show that human zinc finger RNA-binding protein (ZFR) represses the interferon response by regulating alternative pre-mRNA splicing. ZFR expression is tightly controlled during macrophage development; monocytes express truncated ZFR isoforms, while macrophages induce full-length ZFR to modulate macrophage-specific alternative splicing. Interferon-stimulated genes are constitutively activated by ZFR depletion, and immunostimulation results in hyper-induction of interferon β (IFNβ/ IFNB1 ). Through whole-genome analyses, we show that ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay of histone variant macroH2A1/H2AFY mRNAs. Together, our data suggest that regulation of ZFR in macrophage differentiation guards against aberrant interferon responses and reveal a network of mRNA processing and decay that shapes the transcriptional response to infection. Type I interferon signaling is critical for the control of infection. Here the authors show that zinc finger RNA-binding protein (ZFR) can control type I interferon responses, and that this control is itself regulated by distinct ZFR truncation patterns that differ between monocytes and macrophages.

Microglia are resident innate immune cells in the central nervous system (CNS) that provides anti-microbial protection but also promote neuroinflammation. BRD4 is a chromatin reader that binds to acetylated histones and directs transcription of numerous genes. However, it is unknown whether and how BRD4 regulates microglia function. We addressed the role of microglia and BRD4 in a neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. It was reported earlier that in EAE, upon initial T cell activation in the peripheral lymphoid organs, CD4 + T cells migrate to CNS and are reactivated by resident or migratory antigen presenting cells resulting in full manifestation of EAE (Rossi and Constantin, Front Immunol 7:506, 2016), (Plastini et al., Front Cell Neurosci 14:269, 2020). Using conditional deletion of Brd4 in CD4 T cells, we reveal that BRD4 regulates T helper cell differentiation and promotes T cell migration to CNS resulting in EAE. It remained unclear whether resident microglia are capable of reactivating migrating T cells to the CNS and if BRD4 plays a role in the process. To determine the role of microglial BRD4 in EAE, we constructed conditional knockout mice lacking Brd4 (Brd4cKO) in microglia. RNA-seq analysis showed that Brd4 deletion led to the downregulation of many microglia genes in both naive and EAE conditions. Consequently, Brd4cKO mice had markedly reduced EAE pathology, namely reduced paralysis, absence of axonal demyelination and inhibited expression of inflammatory cytokines. In vehicle treated mice (vehicle) abundant number of T cells were found to be near microglia that may lead to T cell- microglia interaction and T cell reactivation. In contrast, the number of T cells detected in the CNS of Brd4cKO mice was much fewer. This may lead to reduced T cell- microglia interaction, failure of T cells to get reactivated and hence failed to achieve full manifestation of EAE. These results demonstrate that microglia are critically involved in EAE disease progression for which BRD4 is essential. In summary, BRD4 directs transcription of genes defining microglia function. By so doing BRD4 promotes demyelination and neuroinflammation to exacerbate EAE.

Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte–DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higherorder chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.

The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.