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| Open AccessThe chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis
The epigenetic changes underlying the heterogeneity of RA disease presentation have been the subject of intense scrutiny. In this study, the authors use multiple single-cell sequencing datasets to define ‘chromatin superstates’ in patients with RA, which associate with distinct transcription factors and disease phenotypes.
- Kathryn Weinand
- , Saori Sakaue
- & Soumya Raychaudhuri
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open AccessFoxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity
Cell lineage specification involves substantial chromatin conformation reorganization. Here, the authors integrate in-situ Hi-C and PLAC-seq to map the dynamic changes in 3D chromatin structure during Treg cell differentiation. Furthermore, the authors further characterize the role of Foxp3 in the establishment of Treg-specific chromatin interactions by different Foxp3-mutant mouse lines.
- Zhi Liu
- , Dong-Sung Lee
- & Jesse R. Dixon
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Article
| Open AccessCTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells
The role of 3D genome organization is not well understood in the transcriptional regulation of dendritic cells. Here the authors show that activation of dendritic cells in vitro induces dynamic reprogramming of the chromatin looping and enhancer activity linked to changes in gene expression and implicates a role for the chromatin architecture protein CTCF in the inflammatory response of dendritic cells.
- Bobae Yang
- , Sueun Kim
- & Hyoung-Pyo Kim
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Article
| Open AccessNsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis
Th17 cells produce a range of characteristic Th17 type cytokines and express transcription factors governed by epigenetic regulation to engage the Th17 programme. Here the authors implicate the RNA 5- methylcytosine (m5C) methyltransferase Nsun2 in Th17 cells and the promotion of colitis in a murine model.
- Wen-Lan Yang
- , Weinan Qiu
- & Yun-Gui Yang
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Article
| Open AccessSetd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation
Treg cells can be functionally altered by epigenetic modulators. Here the authors show that the histone H3K36 methyltransferase Setd2 is important for the survival of Treg cells and for the regulation of IL-33 mediated Th2 responses in mice and SETD2 expression is increased in Treg cells from human colorectal cancer tissue.
- Zhaoyun Ding
- , Ting Cai
- & Ju Qiu
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Article
| Open AccessPostnatal expansion of mesenteric lymph node stromal cells towards reticular and CD34+ stromal cell subsets
Lymph nodes in various locations of the body differ in their cell composition and gene expression signatures. Here authors show that the rapid postnatal expansion of lymph nodes is governed by CD34 + stromal cells and fibroblastic reticular stromal cell progenitors, distinguished by intrinsic, microbiome-independent core epigenetic blueprints.
- Joern Pezoldt
- , Carolin Wiechers
- & Jochen Huehn
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Article
| Open AccessKinetics of mRNA nuclear export regulate innate immune response gene expression
The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.
- Diane Lefaudeux
- , Supriya Sen
- & Sri Kosuri
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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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| 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 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 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 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 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 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 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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| 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 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 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 AccessSTAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus
BATF is a transcription factor that is needed for IL-9 production by T helper 9 cells. Here the authors show that STAT5 is needed at the Il9 locus to enable BATF to function in this manner and that this interaction can reprogram other T helper subsets into IL-9 producing cells, thus regulating the immune response to disease.
- Yongyao Fu
- , Jocelyn Wang
- & Mark H. Kaplan
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Article
| Open AccessAntibody-secreting cell destiny emerges during the initial stages of B-cell activation
The development of activated B cells into antibody-secreting cells (ASC) is a critical step for humoral immunity. Here the authors show, using adoptive transfers and single cell RNA sequencing, that commitment to ASC occurs soon following B cell activation, and is coordinated by specific transcriptome programs and proliferation kinetics.
- Christopher D. Scharer
- , Dillon G. Patterson
- & Jeremy M. Boss
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Article
| Open AccessHistone deacetylase 3 controls lung alveolar macrophage development and homeostasis
Alveolar macrophages are known to derive from embryonic precursors although the regulation of this process is poorly understood. Here the authors propose a key role for histone deacetylase 3 as an epigenetic regulator of lung alveolar macrophage development.
- Yi Yao
- , Queping Liu
- & Qing-Sheng Mi
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Article
| Open AccessDNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner
Formation of γH2Ax serves as a checkpoint for double-strand break (DSB) repair pathways. Here the authors reveal via integrated chromatin analysis that γH2Ax domains are established by chromosomal contacts with the DSB site.
- Patrick L. Collins
- , Caitlin Purman
- & Eugene M. Oltz
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Article
| Open AccessSexual-dimorphism in human immune system aging
Whether the immune system aging differs between men and women is barely known. Here the authors characterize gene expression, chromatin state and immune subset composition in the blood of healthy humans 22 to 93 years of age, uncovering shared as well as sex-unique alterations, and create a web resource to interactively explore the data.
- Eladio J. Márquez
- , Cheng-han Chung
- & Duygu Ucar
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| Open AccessAttenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis
The transcription factor Bach2 is critical for T cell differentiation, but how it functions in Treg cells is unclear. Here the authors use a Treg-specific mouse model to show that Bach2 controls homeostasis and function of Treg cells by limiting DNA accessibility and activity of IRF4 in response to TCR signaling.
- Tom Sidwell
- , Yang Liao
- & Axel Kallies
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Article
| Open AccessImmGen report: sexual dimorphism in the immune system transcriptome
Sexual dimorphism is observed frequently in immune disorders, but the underlying insights are still unclear. Here the authors analyze transcriptome and epigenome changes induced by interferon in various mouse immune cell types, and find only a restricted set of sexual dimorphism genes in innate immunity and macrophages.
- Shani Talia Gal-Oz
- , Barbara Maier
- & Tal Shay
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| Open AccessIFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation
Macrophage activation is synergistically controlled by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Here the authors show that IFN-γ promotes macrophage activation not only by activating STAT1-dependent genes, but also by suppressing STAT3-dependent negative feedback regulation downstream of LPS signaling.
- Kyuho Kang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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| Open AccessEOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming
T box transcription factor Eomesodermin (EOMES) is induced when naïve T cells are converted to innate memory T cells in response to cytokines. Here the authors show that EOMES is recruited to RUNX3-bound enhancers and interacts with BRG1 during innate memory T cell formation.
- Nicolas Istaces
- , Marion Splittgerber
- & Abdulkader Azouz
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Article
| Open AccessIron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses
The authors show an important role for iron in B cell proliferation via histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter. Using a measles vaccination murine model, they show that iron-deficient individuals have a significantly reduced antibody response to the vaccine when compared to iron-normal controls.
- Yuhang Jiang
- , Cuifeng Li
- & Xiaoren Zhang
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Article
| Open AccessChromosome dynamics near the sol-gel phase transition dictate the timing of remote genomic interactions
Antibodies are generated through remote genomic interactions involving immunoglobulin variable (VH), diversity (DH) and joining (JH) gene segments. Here the authors develop a strategy to track VH-DHJH motion in B-lymphocytes and provide evidence that chromosome organisation near the sol-gel phase transition dictates the timing of genomic interactions to orchestrate gene expression and somatic recombination.
- Nimish Khanna
- , Yaojun Zhang
- & Cornelis Murre
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Article
| Open AccessIdentification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection
Autoreactive T cells are deleted in the thymus via thymic negative selection and Bim-mediated apoptosis. Here the authors identify a cis-acting enhancer, EBAB, that is essential for proper Bim expression and apoptosis induction, and show that EBAB deficiency specifically impairs thymic negative selection without affecting peripheral T cell homeostasis.
- Miki Arai Hojo
- , Kyoko Masuda
- & Shinpei Kawaoka
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Article
| Open AccessmiR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate
The inability of T cells to properly mount anti-tumour immunity underlies failed cancer immune surveillance or therapy. Here the authors show that a microRNA, miR-155, suppresses Ship1 phosphatase expression to modulate epigenetic reprogramming of CD8 T cell differentiation via the Phf19/PRC2 axis, thereby implicating a novel aspect of cancer immunity regulation.
- Yun Ji
- , Jessica Fioravanti
- & Luca Gattinoni
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Article
| Open AccessLoss of TET2 and TET3 in regulatory T cells unleashes effector function
Loss of TET proteins in immune cell populations is known to result in immunopathology. Here the authors show that deficiency of Tet2 and Tet3 proteins, specifically in the CD4+ FoxP3+ Treg lineage, results in a dominant pathology in which ex-Treg cells and bystander T cells gain aberrant effector function.
- Xiaojing Yue
- , Chan-Wang J. Lio
- & Anjana Rao
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Article
| Open AccessMettl3-mediated mRNA m6A methylation promotes dendritic cell activation
Here the authors examine how m6A modification is involved in innate immunity. They show that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function, and in promoting DC-based T cells responses.
- Huamin Wang
- , Xiang Hu
- & Xuetao Cao
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Article
| Open AccessPRMT5 is essential for B cell development and germinal center dynamics
Protective antibody responses depend critically on proper B cell development and differentiation at multiple stages. Here the authors show that a protein arginine methyltransferase, Prmt5 uses multiples pathways to prevent death of immature B cells, yet modulates, in p53-independent manners, the survival and differentiation of mature B cells.
- Ludivine C. Litzler
- , Astrid Zahn
- & Javier M. Di Noia
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Article
| Open AccessInterleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape
Regulatory T (Treg) cells are developed in the thymus, and are essential for suppressing detrimental autoimmunity. Here the authors show, using mice with dampened interleukin 2 (IL-2) signaling, that IL-2 helps position the pioneer factor SATB1 to control genome-wide chromatin accessibility to facilitate Treg cell lineage commitment in the thymus.
- Laurent Chorro
- , Masako Suzuki
- & Grégoire Lauvau
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Article
| Open AccessA conserved enhancer regulates Il9 expression in multiple lineages
Interleukin-9 (IL-9) is important for allergy, autoimmunity and tumor immunity, but how its expression is regulated is unclear. Here the authors show the essential function of an enhancer, CNS-25 in mouse and CNS-18 in human, for IL-9 expression, with the deletion of this enhancer severely hampering IL-9 production in mice or human cells.
- Byunghee Koh
- , Amina Abdul Qayum
- & Mark H. Kaplan
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Article
| Open AccessSUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2
Interleukin-17 (IL-17)-secreting CD4 T cells (Th17) are induced by the master transcription factor RORγt, and are important for anti-fungal immunity and inflammatory responses. Here the authors show that Ubc9-mediated SUMOylation of RORγt induces HDAC2 binding to IL-17 promoter for suppressing IL-17 production in Th17 cells.
- Amir Kumar Singh
- , Prashant Khare
- & K. Venuprasad
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Article
| Open AccessBRWD1 orchestrates epigenetic landscape of late B lymphopoiesis
B-cell development is tightly regulated by transcription programs that are coordinated by transcription factors (TF) and locus accessibility. Here the authors show that, in mice and humans, the epigenetic reader BRWD1 inhibits and promotes the accessibility of enhancers for early and late B lymphopoiesis, respectively.
- Malay Mandal
- , Mark Maienschein-Cline
- & Marcus R. Clark
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Article
| Open AccessStage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development
The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of Cd4 in thymocytes but are dispensable for its sustained expression in peripheral T cells.
- Priya D. Issuree
- , Kenneth Day
- & Dan R. Littman
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Article
| Open AccessEpigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy
Immunoglobulin E (IgE)-mediated food allergy is a major issue that affects 2–10% of infants. Here the authors study the epigenetic regulation of the naive CD4+ T cell activation response among children with IgE-mediated food allergy finding epigenetic dysregulation in the early stages of signal transduction through the T cell receptor complex.
- David Martino
- , Melanie Neeland
- & Richard Saffery
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Article
| Open AccessTCR signal strength controls thymic differentiation of iNKT cell subsets
Invariant natural killer T (iNKT) cells can be subsetted by their cytokine profiles, but how they develop in the thymus is unclear. Here the authors show, by analysing mice carrying mutant Zap70 genes, that T cell receptor signaling strength induces epigenetic changes of genes to modulate iNKT lineages.
- Kathryn D. Tuttle
- , S. Harsha Krovi
- & Laurent Gapin
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Article
| Open AccessB cell activation and plasma cell differentiation are inhibited by de novo DNA methylation
DNA methylation is known to contribute to B cell differentiation, but de novo methylation has not been studied in this context. Here the authors use a conditional Dnmt3a/b knockout mouse to map the function of de novo DNA methylation in B cell differentiation and the development of humoral immunity.
- Benjamin G. Barwick
- , Christopher D. Scharer
- & Jeremy M. Boss
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Article
| Open AccessPlasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs
During B cell differentiation, the role of different genomic loci in transcriptional and epigenetic regulation in vivo is not well defined. Here the authors use an in vivo B cell differentiation model to map cellular division-dependent cis-regulatory element road map with ATAC-seq.
- Christopher D. Scharer
- , Benjamin G. Barwick
- & Jeremy M. Boss
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Article
| Open AccessBcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma
Th2 cells are critical in the resolution of helminth infection and allergy. Here the authors show that Bcl11b is required to license the Th2 program of helper T cell differentiation and restrict alternate lineage gene expression using in vivo models of helminth infection and asthma.
- Kyle J. Lorentsen
- , Jonathan J. Cho
- & Dorina Avram
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Article
| Open AccessEpigenetic activation during T helper 17 cell differentiation is mediated by Tripartite motif containing 28
T help 17 (Th17) cells are important mediators for both protective and pathogenic immune reactions, but how their functions are regulated at the epigenetic level is not understood. Here the authors show that TRIM28, a cofactor for transcriptional regulation, is important for epigenetic activation of Th17-related gene loci during Th17 response.
- Yu Jiang
- , Ying Liu
- & Chen Dong