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Background The BIN1 locus contains the second-most significant genetic risk factor for late-onset Alzheimer’s disease. BIN1 undergoes alternate splicing to generate tissue- and cell-type-specific BIN1 isoforms, which regulate membrane dynamics in a range of crucial cellular processes. Whilst the expression of BIN1 in the brain has been characterized in neurons and oligodendrocytes in detail, information regarding microglial BIN1 expression is mainly limited to large-scale transcriptomic and proteomic data. Notably, BIN1 protein expression and its functional roles in microglia, a cell type most relevant to Alzheimer’s disease, have not been examined in depth. Methods Microglial BIN1 expression was analyzed by immunostaining mouse and human brain, as well as by immunoblot and RT-PCR assays of isolated microglia or human iPSC-derived microglial cells. Bin1 expression was ablated by siRNA knockdown in primary microglial cultures in vitro and Cre-lox mediated conditional deletion in adult mouse brain microglia in vivo. Regulation of neuroinflammatory microglial signatures by BIN1 in vitro and in vivo was characterized using NanoString gene panels and flow cytometry methods. The transcriptome data was explored by in silico pathway analysis and validated by complementary molecular approaches. Results Here, we characterized microglial BIN1 expression in vitro and in vivo and ascertained microglia expressed BIN1 isoforms. By silencing Bin1 expression in primary microglial cultures, we demonstrate that BIN1 regulates the activation of proinflammatory and disease-associated responses in microglia as measured by gene expression and cytokine production. Our transcriptomic profiling revealed key homeostatic and lipopolysaccharide (LPS)-induced inflammatory response pathways, as well as transcription factors PU.1 and IRF1 that are regulated by BIN1. Microglia-specific Bin1 conditional knockout in vivo revealed novel roles of BIN1 in regulating the expression of disease-associated genes while counteracting CX3CR1 signaling. The consensus from in vitro and in vivo findings showed that loss of Bin1 impaired the ability of microglia to mount type 1 interferon responses to proinflammatory challenge, particularly the upregulation of a critical type 1 immune response gene, Ifitm3 . Conclusions Our convergent findings provide novel insights into microglial BIN1 function and demonstrate an essential role of microglial BIN1 in regulating brain inflammatory response and microglial phenotypic changes. Moreover, for the first time, our study shows a regulatory relationship between Bin1 and Ifitm3 , two Alzheimer’s disease-related genes in microglia. The requirement for BIN1 to regulate Ifitm3 upregulation during inflammation has important implications for inflammatory responses during the pathogenesis and progression of many neurodegenerative diseases. Graphical Abstract

PU.1, a transcription factor member of the E26 transformation-specific family, affects the function of a variety of immune cells in several physiological and pathological conditions. Previous studies studying the role of PU.1 in pathological conditions have mainly focused on immune system-related cancers, and a series of articles have confirmed that PU.1 mutation can induce a variety of immune cell-related malignancies. The underlying mechanism has also been extensively validated. However, the role of PU.1 in other major immune system-related diseases, namely, systemic autoimmune diseases, is still unclear. It was only in recent years that researchers began to gradually realize that PU.1 also played an important role in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE). This review article summarizes the findings of recent studies that investigated the role of PU.1 in various autoimmune diseases and the related underlying mechanisms. Furthermore, it presents new ideas and provides insight into the role of PU.1 as a potential treatment target for autoimmune diseases and highlights existing research problems and future research directions in related fields.

The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB–dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB–dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.

The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects onmultiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.

Abstract Objectives Rosai-Dorfman disease (RDD) is a rare disorder characterized by the accumulation of large S100 protein-positive histiocytes that typically exhibit emperipolesis. The recently reported expression of Oct-2 in RDD histiocytes led us to explore whether PU.1, a transcription factor that is required for monocyte and B-cell development, could similarly function as a diagnostic marker in RDD. Methods We evaluated the expression of PU.1 and Oct-2 using immunohistochemistry in 19 patients diagnosed with RDD involving nodal, extranodal, and cutaneous sites. Results Both PU.1 and Oct-2 were positive in all cases studied, with a strong intensity of staining in 84% of cases in which more than 50% of the lesional cells were positive. In three patients, both markers showed weak to moderate intensity of staining. Two patients had concomitant RDD and Langerhans cell histiocytosis in which PU.1 stained both types of histiocytes while Oct-2 stained only the RDD component. Conclusions PU.1 emerged as a robust marker with crisp nuclear staining in RDD histiocytes as well as in engulfed inflammatory cells. Strong coexpression of PU.1 and Oct-2 is a useful diagnostic marker in differentiating histiocytic/dendritic cell proliferations.

ANP32B, a member of the acidic leucine‐rich nuclear phosphoprotein 32 kDa (ANP32) family of proteins, is critical for normal development because its constitutive knockout mice are perinatal lethal. It is also shown that ANP32B acts as a tumor‐promoting gene in some kinds of cancer such as breast cancer and chronic myelogenous leukemia. Herein, we observe that ANP32B is lowly expressed in B‐cell acute lymphoblastic leukemia (B‐ALL) patients, which correlates with poor prognosis. Furthermore, we utilized the N‐myc or BCR‐ABLp190‐induced B‐ALL mouse model to investigate the role of ANP32B in B‐ALL development. Intriguingly, conditional deletion of Anp32b in hematopoietic cells significantly promotes leukemogenesis in two B‐ALL mouse models. Mechanistically, ANP32B interacts with purine rich box‐1 (PU.1) and enhances the transcriptional activity of PU.1 in B‐ALL cells. Overexpression of PU.1 dramatically suppresses B‐ALL progression, and highly expressed PU.1 significantly reverses the accelerated leukemogenesis in Anp32b‐deficient mice. Collectively, our findings identify ANP32B as a suppressor gene and provide novel insight into B‐ALL pathogenesis. Loss of Anp32b promotes B‐cell acute lymphoblastic leukemia (B‐ALL) development in mice. ANP32B enhances PU.1 activity to regulate B‐ALL leukemogenesis.

Microglia progenitors seed the central nervous system from the yolk sac, but little is known about the origin of non-parenchymal macrophages. Prinz and colleagues demonstrate that these macrophages in the central nervous system are related to but distinct from microglia and are largely of embryonic origin. Perivascular, subdural meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It was assumed that they have a high turnover from blood-borne monocytes. However, using parabiosis and fate-mapping approaches in mice, we found that CNS macrophages arose from hematopoietic precursors during embryonic development and established stable populations, with the notable exception of choroid plexus macrophages, which had dual origins and a shorter life span. The generation of CNS macrophages relied on the transcription factor PU.1, whereas the MYB, BATF3 and NR4A1 transcription factors were not required.

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

Microglia are brain-resident macrophages playing pivotal roles in central nervous system (CNS) development and homeostasis. Yet, the cellular and molecular basis governing microglia maintenance remains largely unknown. Here, by utilizing a visible conditional knockout allele of pu.1/spi1b gene (the master regulator for microglia/macrophage lineage development) to generate mosaic microglia populations in adult zebrafish, we show that while pu.1 -deficient microglia are immediately viable, they are less competitive, and chronically eliminated through Tp53-mediated cell competition. Interestingly, when conditionally inactivating Pu.1 in adult spi-b (the orthologue of mouse Spi-b ) null mutants, microglia are rapidly depleted via apoptosis, suggesting that Pu.1 and Spi-b regulate microglia maintenance in a dosage-dependent manner. The dosage-dependent regulation of microglia maintenance by PU.1/SPI1 is evolutionarily conserved in mice, as shown by conditionally inactivating single and both Spi1 alleles in microglia, respectively. Collectively, our study reveals the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleosts and mammals.

A recent study by Ayata et al. (2025) reveals that the transcription factor PU.1 acts as a molecular switch that determines whether microglia protect against or worsen Alzheimer’s disease pathology, with lower PU.1 levels promoting beneficial microglial states that reduce amyloid burden and neuroinflammation.