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| Open AccessOpposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
IL-9-producing CD4 T (Th9) cells have been implicated in allergy and tumor immunity, but how their differentiation is regulated by TGFβ is still unclear. Here the authors show that two transcription factors, DBP and E2F8, institute opposing effects on IL-9 expression downstream of TGFβ/Smad3 linker region-mediated signaling in activated mouse T cells to modulate antitumor responses.
- Sang-A Park
- , Yun-Ji Lim
- & WanJun Chen
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Article
| Open AccessThe immune factors driving DNA methylation variation in human blood
Many studies assess epigenetic marks in white blood cells, but it is unclear how much immune factors affect the epigenome. Here, the authors show that fine-scale blood cell composition and cytomegalovirus infection affect the DNA methylome of adults.
- Jacob Bergstedt
- , Sadoune Ait Kaci Azzou
- & Lluis Quintana-Murci
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Article
| Open AccessMulticellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis
Uveitis is a complex autoimmune inflammatory disease of the eye and defining molecules involved is a priority. Here the authors use scRNA sequencing in mouse experimental autoimmune uveitis (EAU) and show PIM1 promotes the imbalance of Th17 and Treg cells, and find elevated PIM-1 in human uveitis disease.
- He Li
- , Lihui Xie
- & Wenru Su
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Article
| Open AccessInterleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
- Polychronis Pavlidis
- , Anastasia Tsakmaki
- & Nick Powell
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Article
| Open AccessChromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers
Here the authors show the identity of CD4 + CD8 + double-positive (DP) thymocytes changes upon loss of chromatin organizer Satb1, which controls the expression of cell identity genes by regulating super-enhancers via 3D genome architecture.
- Delong Feng
- , Yanhong Chen
- & Bingtao Hao
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Article
| Open AccessSingle cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
- Vincent Geldhof
- , Laura P. M. H. de Rooij
- & Peter Carmeliet
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Article
| Open AccessAn anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish
Macrophages are important for tissue regeneration after injury. Here, using a single cell sequencing approach in a zebrafish injury model, the authors show that macrophages transition through a three stage process during tissue regeneration after hair cell damage.
- Nicolas Denans
- , Nhung T. T. Tran
- & Tatjana Piotrowski
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open AccessCancer co-opts differentiation of B-cell precursors into macrophage-like cells
The tumour microenvironment has been shown to change the phenotypes and functionality of immune cells to enable tumour propagation. Here authors show that cancers can derail B cell development to give rise to macrophage-like cells, contributing to cancer progression and metastasis via disabling local T cell response.
- Chen Chen
- , Bongsoo Park
- & Arya Biragyn
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Article
| Open AccessHeterogeneity and transcriptome changes of human CD8+ T cells across nine decades of life
The characterisation of T cells during aging is important to predict functional outcomes in vaccination or infection. Here the authors use flow cytometry and scRNA sequencing to transcriptionally age CD8 T cells and then use a machine learning model to interpret cell age from transcriptional profiles.
- Jian Lu
- , Raheel Ahmad
- & Nan-ping Weng
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Article
| Open AccessEarly macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.
- L. Orliaguet
- , T. Ejlalmanesh
- & F. Alzaid
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Article
| Open AccessTemporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-β signalling which could promote the anti-tumour response.
- Rachael M. Zemek
- , Wee Loong Chin
- & W. Joost Lesterhuis
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Article
| Open AccessCircular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription
Innate lymphoid cells (ILC) have been shown to be involved in a range of inflammatory contexts but how their cellular lineage is regulated is not fully established. Here the authors show a role for circular RNA circTmem241 in the differentiation of ILC3 via initiation of Elk3 transcription.
- Nian Liu
- , Jiacheng He
- & Zusen Fan
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Article
| Open AccessNotch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation
Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.
- Carys A. Croft
- , Anna Thaller
- & James P. Di Santo
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Article
| Open AccessLy6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage
The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.
- Konstantin Lutz
- , Andrea Musumeci
- & Anne B. Krug
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Article
| Open AccessCXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes
The chemokine, CXCL4, is proposed to enhance Toll-like receptor (TLR) signaling by facilitating TLR ligand import. Here the authors show that CXCL4 also synergizes with TLR8 to promote the activation of TBK1 and IKKε and induce epigenetic remodeling of relevance inflammatory genes to enhance inflammatory responses in human monocytes.
- Chao Yang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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Article
| Open AccessSingle-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure.
- Roy Oelen
- , Dylan H. de Vries
- & Monique G. P. van der Wijst
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Article
| Open AccessRobust temporal map of human in vitro myelopoiesis using single-cell genomics
The myeloid lineage is central to homeostasis and immunity. The authors provide an atlas of human iPSC-to-myeloid cell differentiation and demonstrate that the in vitro system recapitulates yolk sac differentiation, opening new avenues to human myelopoiesis.
- Clara Alsinet
- , Maria Nascimento Primo
- & Roser Vento-Tormo
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Article
| Open AccessThe timing of differentiation and potency of CD8 effector function is set by RNA binding proteins
RNA binding proteins (RBP) have a function in T cell activation and differentiation. Here the authors show that in the absence of two RBPs, ZFP36 and ZFP36L1, T cells acquire more rapidly superior effector capabilities, showing a limiting function for RBP in T cell activation and differentiation.
- Georg Petkau
- , Twm J. Mitchell
- & Martin Turner
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Article
| Open AccessT cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling
The strength and duration of interleukin-2 (IL-2) signals is known to regulate T cell memory. Here the authors show that T cell receptor signalling strength controls the requirement for IL-2 signals to form CD8+ T cell memory with high functional activity and a wide range of genes with open chromatin regions.
- Shu Shien Chin
- , Erik Guillen
- & Grégoire Lauvau
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Article
| Open AccessPD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity
Phenotypic and functional states of dendritic cells critically influence the outcome of cancer and inflammation. Authors here show by single cell transcriptomics and in vitro validation assays that dichotomous PD-L1 and ICOSL expression assign dendritic cells to secretory and helper functions, with respective predominance of inflammatory cytokine expression or T helper cytokine induction.
- Caroline Hoffmann
- , Floriane Noel
- & Vassili Soumelis
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Article
| Open AccessCD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element
Epigenetic states that are established during thymic T cell development influence functionality of mature T cells. Authors here show that early developmental programming of the Cd4 locus is comprised of DNA-demethylation at a specific stimulus-responsive element, which allows long-term maintenance of activator histone H3K4 trimethylation and transcription.
- Athmane Teghanemt
- , Priyanjali Pulipati
- & Priya D. Issuree
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Article
| Open AccessEnhanced cell deconvolution of peripheral blood using DNA methylation for high-resolution immune profiling
Deconvolution algorithms facilitate studying cell type-specific changes using bulk data from complex tissues. Here, the authors present a deconvolution method that predicts DNA methylation levels in 12 leukocyte subtypes using human microarray data and apply it to various examples.
- Lucas A. Salas
- , Ze Zhang
- & Brock C. Christensen
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Article
| Open AccessA disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
Mutations in the non-coding RNA RMRP cause primary immunodeficiency. Robertson et al show that a disease-associated mutation in RMRP impairs pre-ribosomal RNA processing and reduces ribosome abundance, establishing this disorder as a ribosomopathy.
- Nic Robertson
- , Vadim Shchepachev
- & David Tollervey
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Article
| Open AccessPostmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation
Postmortem analyses provide useful information for COVID-19 etiology. Here the authors profile 22 deceased severe COVID-19 patients with transcriptomic and histological approaches to find correlations between the presence of viral antigens with lymphocyte suppression yet myeloid activation, hinting distinct functions of these cells during pathogenesis.
- Haibo Wu
- , Peiqi He
- & Cheng Sun
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Article
| Open AccessOxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages
Redox-dependent regulation plays a key role in the pathogenesis of acute lung injury, but its mechanism is unclear. Here the authors show Grx1-regulated S-glutathionylation of FABP5 controls macrophage inflammation and alleviates acute lung injury.
- Yuxian Guo
- , Yaru Liu
- & Xue Zhang
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Article
| Open AccessProximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome
Integrating functional data with GWAS loci can help interpret the function of genetic variants associated with disease. Here the authors map cis and trans methylation QTL in CD4 + T cells from patients and colocalize with GWAS loci in order to interpret genetic variants associated with multiple sclerosis.
- Tina Roostaei
- , Hans-Ulrich Klein
- & Philip L. De Jager
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Article
| Open AccessA DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells
The differentiation of naive T cells to immune suppressing induced regulatory T (iTreg) cells requires TGF-beta-1 and downregulation of mTORC1 activity, which inhibits mRNA translation. Here the authors show that iTreg cell differentiation uses an alternate mRNA translation mechanism involving translation factors DAP5 and eIF3d.
- Viviana Volta
- , Sandra Pérez-Baos
- & Robert J. Schneider
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Article
| Open AccessCOVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types
Immune cells are important in the pathogenesis of COVID-19. Here the authors assessed the effects of COVID-19-risk variants on gene expression in a range of immune cell types, highlighting their potential to impact the function of diverse immune cell types and influence severe disease.
- Benjamin J. Schmiedel
- , Job Rocha
- & Pandurangan Vijayanand
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Article
| Open AccessZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization
Macrophages employ epigenetic remodeling, especially the regulation of superenhancers (SEs), to promote classical polarization and function; whether liquid-liquid phase separation (LLPS) is involved is not known. Here, the authors show the epigenetic reader ZMYND8 forms condensates to deactivate latent SEs in a spatiotemporal manner and thereby restrict macrophage-mediated inflammation.
- Pan Jia
- , Xiang Li
- & Wei Lu
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Article
| Open AccessTcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture
How CD8+ T cell identity is maintained after exit from the thymus is not fully established. Here the authors use multiomics approaches including Hi-C to show that Tcf1 and Lef1 prevent aberrant expression of lineage-inappropriate genes by organizing three-dimensional genomic architecture in CD8+ T cells.
- Qiang Shan
- , Xiang Li
- & Hai-Hui Xue
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Article
| Open AccessCD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells
Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.
- Myung-Chul Kim
- , Nicholas Borcherding
- & Weizhou Zhang
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Article
| Open AccessPolymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases
The Cia21 locus on chromosome 3 has been associated with rheumatoid arthritis severity in females. Here the authors show this locus houses a non-coding polymorphic estrogen receptor binding site and how it regulates neighbouring gene expression of CD2, implicating CD2 signalling in the sexual dimorphism of a variety of T cell-dependent autoimmune diseases.
- Gonzalo Fernandez Lahore
- , Michael Förster
- & Rikard Holmdahl
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Article
| Open AccessSequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells
Natural Killer cell development is controlled by two related transcription factors, Eomes and T-bet. Authors show here that while the two factors share a large proportion of their target genes, they regulate distinct developmental processes by differing in their pattern of expression and in their associated co-factors.
- Jiang Zhang
- , Stéphanie Le Gras
- & Thierry Walzer
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Article
| Open AccessSc-compReg enables the comparison of gene regulatory networks between conditions using single-cell data
Changes in cell state underlie the difference between health and disease. Here, the authors propose a computational framework for the integration of gene expression and chromatin-accessibility data from single cells to identify differences in gene regulation in cell types across two conditions.
- Zhana Duren
- , Wenhui Sophia Lu
- & Wing Hung Wong
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Article
| Open AccessThe trans-omics landscape of COVID-19
COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.
- Peng Wu
- , Dongsheng Chen
- & Gang Chen
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang
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Article
| Open AccessIndispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2
Development of the T cells requires functions from thymic epithelial cells, whose development and function are epigenetically regulated. Here the authors show that inactivation of the polycomb repressive complex 2 (PRC2) alters the H3K27me3 configuration, reduces TEC functions, reveals a specific TEC subset, and hampers T cell development.
- Thomas Barthlott
- , Adam E. Handel
- & Georg A. Holländer
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Article
| Open AccessImmunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model
Dengue virus causes a range of inflammatory pathology but understanding critical phases of the infection during human infection has been challenging. Here the author’s present immunotranscriptomic changes during the acute and clearance phases of a dengue virus serotype 2 human challenge model.
- John P. Hanley
- , Huy A. Tu
- & Sean A. Diehl
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Article
| Open AccessCD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph
The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.
- Luca Hensen
- , Patricia T. Illing
- & Katherine Kedzierska
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Article
| Open AccessA Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages
IFNy can polarize macrophages in the tumour microenvironment to an inflammatory state and thereby contributes to their anti-tumour function. Here the authors show an underlying mechanism in this process is IFNy-driven STAT1 occupancy and activation of NRE1, a regulatory region within the NAMPT gene, thereby implicating inducible NAD salvage synthesis in TAM functions.
- Thomas B. Huffaker
- , H. Atakan Ekiz
- & Ryan M. O’Connell
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Article
| Open AccessConserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
T regulatory (Treg) cells can differentiate into effector Treg (eTreg) cells that might be functional in inflammatory diseases. Using RNA sequencing and epigenetic profiling, the authors show that eTreg signatures in juvenile idiopathic arthritis joints are similar to tumour microenvironment (TME) Treg cells and are affected by tissue-specific epigenetic regulation.
- Gerdien Mijnheer
- , Lisanne Lutter
- & Femke van Wijk
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Article
| Open AccessB1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers
B cell progenitors differentiate into multiple subsets with distinct functions. Here the authors analyze the epigenetic landscapes of sorted B cell subsets using multiple platforms and show that the epigenetic regulator, DNMT3A, is essential for modulating the activity of enhancers critical for B1 and B2 lineage-determining genes.
- Vinay S. Mahajan
- , Hamid Mattoo
- & Shiv Pillai
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Article
| Open AccessCoding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity
Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while C15ORF48 3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.
- Cheryl Q. E. Lee
- , Baptiste Kerouanton
- & Lena Ho
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Article
| Open AccessThe epigenetic pioneer EGR2 initiates DNA demethylation in differentiating monocytes at both stable and transient binding sites
DNA methylation turnover is an essential epigenetic process during development. Here, the authors look at the changes in DNA methylation during the differentiation of post-mitotic human monocytes (MO), and find that EGR2 interacts with TET2 and is required for DNA demethylation at its binding sites; revealing EGR2 as an epigenetic pioneer factor in human MO.
- Karina Mendes
- , Sandra Schmidhofer
- & Michael Rehli
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Article
| Open AccessMitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages
IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
- Jennifer K. Dowling
- , Remsha Afzal
- & Claire E. McCoy
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Article
| Open AccessRNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming
N6-methyladenosine (m6A) is a reversible mRNA modification with important roles in cancer biology and immunoregulation. Here, the authors show that myeloid-specific deletion of Mettl3, the catalytic subunit of the methyltransferase complex, promotes tumor growth and metastasis in preclinical tumor models, influencing macrophage reprogramming and attenuating PD-1 blockade.
- Huilong Yin
- , Xiang Zhang
- & Rui Zhang
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Article
| Open AccessPre-mitotic genome re-organisation bookends the B cell differentiation process
During differentiation, chromosome conformation is remodelled to support lineage-specific transcriptional programs. Here, the authors characterise chromosome conformational changes in B lymphocytes as they differentiate into plasma cells, and provide evidence that chromosome reconfiguration occurs prior to DNA replication and mitosis and guides gene expression that controls differentiation.
- Wing Fuk Chan
- , Hannah D. Coughlan
- & Rhys S. Allan
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Article
| Open AccessSOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation
T helper 17 (Th17) cells are important mediators of inflammatory diseases and fungal infection protection, and are critically regulated by the transcription factor (TF), RORγt. Here the authors identify a new enhancer for RORγt, RORCE2, which synergizes with another TF, Sox5, for binding with RORγt promoter and thereby modulation of RORγt expression.
- Yi Tian
- , Chao Han
- & Yuzhang Wu