KDM1A microenvironment, its oncogenic potential, and therapeutic significance.
Ismail Tayaba,Lee Hyun-Kyung,Kim Chowon,Kwon Taejoon,Park Tae Joo,Lee Hyun-Shik
Epigenetics & chromatin
The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs.
10.1186/s13072-018-0203-3
Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice.
He Xiaomeng,Yu Junjing,Wang Min,Cheng Yang,Han Yanan,Yang Shuo,Shi Guizhi,Sun Lei,Fang Ying,Gong Si-Tang,Wang Zhong,Fu Yang-Xin,Pan Lei,Tang Hong
Nature microbiology
Immune homeostasis is a prerequisite to protective immunity against gastrointestinal infections. In Drosophila, immune deficiency (IMD) signalling (tumour necrosis factor receptor/interleukin-1 receptor, TNFR/IL-1R in mammals) is indispensable for intestinal immunity against invading bacteria. However, how this local antimicrobial immune response contributes to inflammatory regulation remains poorly defined. Here, we show that flies lacking intestinal Bap180 (a subunit of the chromatin-remodelling switch/sucrose non-fermentable (SWI/SNF) complex) are susceptible to infection as a result of hyper-inflammation rather than bacterial overload. Detailed analysis shows that Bap180 is induced by the IMD-Relish response to both enteropathogenic and commensal bacteria. Upregulated Bap180 can feed back to restrain overreactive IMD signalling, as well as to repress the expression of the pro-inflammatory gene eiger (TNF), a critical step to prevent excessive tissue damage and elongate the lifespan of flies, under pathological and physiological conditions, respectively. Furthermore, intestinal targeting of Baf180 renders mice susceptible to a more aggressive infectious colitis caused by Citrobacter rodentium. Together, Bap180 and Baf180 serve as a conserved transcriptional repressor that is critical for the maintenance of innate immune homeostasis in the intestines.
10.1038/nmicrobiol.2017.56
ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.
Cell
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
10.1016/j.cell.2024.04.025
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade.
Shen Jianfeng,Ju Zhenlin,Zhao Wei,Wang Lulu,Peng Yang,Ge Zhongqi,Nagel Zachary D,Zou Jun,Wang Chen,Kapoor Prabodh,Ma Xiangyi,Ma Ding,Liang Jiyong,Song Shumei,Liu Jinsong,Samson Leona D,Ajani Jaffer A,Li Guo-Min,Liang Han,Shen Xuetong,Mills Gordon B,Peng Guang
Nature medicine
ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
10.1038/s41591-018-0012-z
Control of IL-2Ralpha gene expression: structural changes within the proximal enhancer/core promoter during T-cell development.
Nucleic acids research
During T-cell development in thymus, CD25, the IL-2 receptor alpha chain (IL-2Ralpha) is already expressed in early double-negative (DN) thymocytes where commitment to T-cell lineage has been established, but subsequently IL-2Ralpha is dramatically down-regulated for the remainder of T-cell development. The loss of IL-2Ralpha expression after expression of the pre-TCR alpha:beta complex on the cell surface is essential for the later specific responses of mature T cells. Using appropriate mouse models and DMS genomic footprinting, we showed that the TATA box in the core promoter region of the murine IL-2Ralpha locus was occupied only in DN CD25+ T cells. Further, by chromatin immunoprecipitation assays, we evidenced that down-regulation of IL-2Ralpha transcription correlated with (i) loss of the basal transcriptional machinery; (ii) dissociation of histone acetylase p300 and BRG1, a member of the ATP-dependent chromatin remodeling complex SWI/SNF; and (iii) histone N-termini dephosphorylation plus deacetylation. In contrast, occupancy of the proximal enhancer region (positive regulatory region I) was not detected by in vivo genomic footprinting though constitutive accessibility of the promoter region for DNase I digestion both in the DN and double-positive stages correlated with the constitutive association of CBP and PCAF to the IL-2Ralpha core promoter. These results exemplify one mechanism by which a promoter enables transcription to switch on and off during T-cell differentiation.
10.1093/nar/30.9.1944
cBAF complex components and MYC cooperate early in CD8 T cell fate.
Nature
The identification of mechanisms to promote memory T (T) cells has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of T cell generation in vivo, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF). Several components of the cBAF complex are essential for the differentiation of activated CD8 T cells into T effector (T) cells, and their loss promotes T cell formation in vivo. During the first division of activated CD8 T cells, cBAF and MYC frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards T cells, whereas those with low MYC and low cBAF preferentially differentiate towards T cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8 T cells. Treatment of naive CD8 T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of T cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.
10.1038/s41586-022-04849-0
Cutting edge: SWI/SNF mediates antisense Igh transcription and locus-wide accessibility in B cell precursors.
Osipovich Oleg A,Subrahmanyam Ramesh,Pierce Steven,Sen Ranjan,Oltz Eugene M
Journal of immunology (Baltimore, Md. : 1950)
The stepwise process of Ag receptor gene assembly, termed V(D)J recombination, is coordinated during lymphocyte development by sweeping changes in chromatin that permit or deny access to a single recombinase enzyme. We now show that switching/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes are recruited to the Igh locus by an enhancer-dependent process and that these complexes are essential for generating recombinase accessibility throughout the locus. Depletion of SWI/SNF in pro-B cells also inhibits antisense transcription through all clusters of Igh gene segments, a pioneering process that has been implicated in the initial opening of chromatin. We conclude that SWI/SNF complexes play multiple roles in Igh gene assembly, ranging from initial locus activation to the spreading and maintenance of chromatin accessibility over large V(H), D(H), and J(H) domains.
10.4049/jimmunol.0900896
The BRG1 chromatin remodeler regulates widespread changes in gene expression and cell proliferation during B cell activation.
Holley Darcy W,Groh Beezly S,Wozniak Glenn,Donohoe Dallas R,Sun Wei,Godfrey Virginia,Bultman Scott J
Journal of cellular physiology
Widespread changes in gene expression underlie B cell development and activation, yet our knowledge of which chromatin-remodeling factors are essential is limited. Here, we demonstrate that the BRG1 catalytic subunit of SWI/SNF complexes was dispensable for murine B cell development but played an important, albeit selective, role during activation. Although BRG1 was dispensable for CD69 induction and differentiation into plasma cells based on the ability of mutant B cells to undergo hypertrophy and secrete IgM antibodies, it was required for robust cell proliferation in response to activation. Accordingly, BRG1 was required for only ∼100 genes to be expressed at normal levels in naïve B cells but >1,000 genes during their activation. BRG1 upregulated fivefold more genes than it downregulated, and the toll-like receptor pathway and JAK/STAT cytokine-signaling pathways were particularly dependent on BRG1. The importance of BRG1 in B cell activation was underscored by the occurrence of opportunistic Pasteurella infections in conditionally mutant mice. B cell activation has long served as a model of inducible gene expression, and the results presented here identify BRG1 as a chromatin-remodeling factor that upregulates the transcriptome of B cells during their activation to promote rapid cell proliferation and to mount an effective immune response.
10.1002/jcp.24414
Akirin2-Mediated Transcriptional Control by Recruiting SWI/SNF Complex in B Cells.
Tartey Sarang,Takeuchi Osamu
Critical reviews in immunology
Extensive studies in last decade have demonstrated that dynamic control of gene transcription is key in the regulation of inflammatory responses. Although signaling pathways and transcription factors have a central role, growing evidence for the involvement of chromatin in the regulation of gene expression in immune cells has uncovered an evolutionarily conserved role of pathogen recognition and epigenetic regulation. The substantial potential of these responses to drive pathological inflammation and tissue damage highlights the need for rigorous control of these responses. Recently, an evolutionarily conserved nuclear factor, Akirin2, has been identified as an essential link between nuclear factor-κB and chromatin remodelers for transcriptional regulation in macrophages and B cells. In this review, we discuss current understanding of the molecular mechanisms that have instrumental roles in governing the inflammatory response with special emphasis on Akirin2 in B cells.
10.1615/CritRevImmunol.2017019629
Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex.
Tartey Sarang,Matsushita Kazufumi,Vandenbon Alexis,Ori Daisuke,Imamura Tomoko,Mino Takashi,Standley Daron M,Hoffmann Jules A,Reichhart Jean-Marc,Akira Shizuo,Takeuchi Osamu
The EMBO journal
Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.
10.15252/embj.201488447
Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses.
Tartey Sarang,Matsushita Kazufumi,Imamura Tomoko,Wakabayashi Atsuko,Ori Daisuke,Mino Takashi,Takeuchi Osamu
Journal of immunology (Baltimore, Md. : 1950)
Akirin2, an evolutionarily conserved nuclear protein, is an important factor regulating inflammatory gene transcription in mammalian innate immune cells by bridging the NF-κB and SWI/SNF complexes. Although Akirin is critical for Drosophila immune responses, which totally rely on innate immunity, the mammalian NF-κB system is critical not only for the innate but also for the acquired immune system. Therefore, we investigated the role of mouse Akirin2 in acquired immune cells by ablating Akirin2 function in B lymphocytes. B cell-specific Akirin2-deficient (Cd19(Cre/+)Akirin2(fl/fl)) mice showed profound decrease in the splenic follicular (FO) and peritoneal B-1, but not splenic marginal zone (MZ), B cell numbers. However, both Akirin2-deficient FO and MZ B cells showed severe proliferation defect and are prone to undergo apoptosis in response to TLR ligands, CD40, and BCR stimulation. Furthermore, B cell cycling was defective in the absence of Akirin2 owing to impaired expression of genes encoding cyclin D and c-Myc. Additionally, Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells. Cd19(Cre/+)Akirin2(fl/fl) mice showed impaired in vivo immune responses to T-dependent and -independent Ags. Collectively, these results demonstrate that Akirin2 is critical for the mitogen-induced B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex, further emphasizing the significant function of Akirin2 not only in the innate, but also in adaptive immune cells.
10.4049/jimmunol.1500373
Akirin interacts with Bap60 and 14-3-3 proteins to regulate the expression of antimicrobial peptides in the kuruma shrimp (Marsupenaeus japonicus).
Liu Ning,Wang Xian-Wei,Sun Jie-Jie,Wang Lei,Zhang Hong-Wei,Zhao Xiao-Fan,Wang Jin-Xing
Developmental and comparative immunology
Akirin is a recently discovered nuclear factor that plays important roles in innate immune responses. Akirin is a positive regulator of the NF-κB factor of the Drosophila immune deficiency (IMD) pathway, which shares extensive similarities with the mammalian tumor necrosis factor receptor (TNFR) signaling pathway. However, some studies found that the NF-κB transcriptional targets were also strongly repressed in akirin2 knockout mice following TLR, IL-1β and TNFα treatment. Therefore, the function of Akirin in the immune response requires further clarification. In this study, an Akirin homolog in the kuruma shrimp (Marsupenaeus japonicus) was identified. It was mainly expressed in hemocytes, heart and intestines. The expression of Akirin was upregulated by challenge with the Gram-negative bacterium Vibrio anguillarum, but was not significantly influenced by challenge with the Gram-positive bacterium Staphylococcus aureus. Knockdown of Akirin suppressed the expression of several IMD-Relish target effectors (antimicrobial peptides, AMPs). The limited regulating spectrum of Akirin might be associated with Bap60, a component of the Brahma (SWI/SNF) ATP-dependent chromatin-remodeling complex. In addition, Akirin also interacts with 14-3-3, which inhibited the expression of Akirin-target AMPs. The results suggested that Akirin is involved in the IMD-Relish pathway by interacting with Relish. The interaction of Akirin with Bap60 positively regulated the Akirin-Relish function, and its interaction with 14-3-3 negatively regulated the Akirin-Relish function.
10.1016/j.dci.2015.10.015
Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling.
Bonnay François,Nguyen Xuan-Hung,Cohen-Berros Eva,Troxler Laurent,Batsche Eric,Camonis Jacques,Takeuchi Osamu,Reichhart Jean-Marc,Matt Nicolas
The EMBO journal
The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes.
10.15252/embj.201488456
The SWI/SNF chromatin-remodeling complex modulates peripheral T cell activation and proliferation by controlling AP-1 expression.
Jeong Seung Min,Lee Changjin,Lee Sung Kyu,Kim Jieun,Seong Rho Hyun
The Journal of biological chemistry
The SWI/SNF chromatin-remodeling complex has been implicated in the activation and proliferation of T cells. After T cell receptor signaling, the SWI/SNF complex rapidly associates with chromatin and controls gene expression in T cells. However, the process by which the SWI/SNF complex regulates peripheral T cell activation has not been elucidated. In this study, we show that the SWI/SNF complex regulates cytokine production and proliferation of T cells. During T cell activation, the SWI/SNF complex is recruited to the promoter of the transcription factor AP-1, and it increases the expression of AP-1. Increased expression of the SWI/SNF complex resulted in enhanced AP-1 activity, cytokine production, and proliferation of peripheral T cells, whereas knockdown of the SWI/SNF complex expression impaired the AP-1 expression and reduced the activation and proliferation of T cells. Moreover, mice that constitutively expressed the SWI/SNF complex in T cells were much more susceptible to experimentally induced autoimmune encephalomyelitis than the normal mice were. These results suggest that the SWI/SNF complex plays a critical role during T cell activation and subsequent immune responses.
10.1074/jbc.M109.026997
A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function.
Immunity
Regulatory T (Treg) cells play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg cell development and function are dependent on the transcription factor Foxp3. Here, we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome-remodeling and SAGA chromatin-modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc) BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg cell function in vitro. Brd9 ablation compromised Treg cell function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg cell function.
10.1016/j.immuni.2020.06.011
Loss of PBAF promotes expansion and effector differentiation of CD8 T cells during chronic viral infection and cancer.
Cell reports
During chronic viral infection and cancer, it has been established that a subset of progenitor CD8 T cells continuously gives rise to terminally exhausted cells and cytotoxic effector cells. Although multiple transcriptional programs governing the bifurcated differentiation trajectories have been previously studied, little is known about the chromatin structure changes regulating CD8 T cell-fate decision. In this study, we demonstrate that the chromatin remodeling complex PBAF restrains expansion and promotes exhaustion of CD8 T cells during chronic viral infection and cancer. Mechanistically, transcriptomic and epigenomic analyses reveal the role of PBAF in maintaining chromatin accessibility of multiple genetic pathways and transcriptional programs to restrain proliferation and promote T cell exhaustion. Harnessing this knowledge, we demonstrate that perturbation of PBAF complex constrained exhaustion and promoted expansion of tumor-specific CD8 T cells resulting in antitumor immunity in a preclinical melanoma model, implicating PBAF as an attractive target for cancer immunotherapeutic.
10.1016/j.celrep.2023.112649
The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8 T cells.
Immunity
CD8 T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8 T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1 progenitor Tex cells to more differentiated TCF-1 Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.
10.1016/j.immuni.2023.05.008
T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-gamma promoter are Stat4 dependent.
Zhang Fuping,Boothby Mark
The Journal of experimental medicine
Transcriptional competence of the interferon-gamma (IFN-gamma) locus is enhanced as Th1 effectors develop from naive CD4 T lymphocytes; conversely, this gene is repressed during Th2 differentiation. We now show that the Switch (Swi)-sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited, and positioned nucleosomes are remodeled, in a Th1-specific manner that is dependent on the transcription factor Stat4 and calcineurin phosphatase activity. Interference with specific components of mammalian Swi-SNF complexes decreased CD4 T cell differentiation into IFN-gamma-positive Th1 cells. These findings reveal a collaborative mechanism of IFN-gamma gene regulation during Th1 differentiation and suggest that a Th1-specific chromatin structure is created by early recruitment of Swi-SNF complexes and nucleosome remodeling dependent on Stat4 and calcineurin activation.
10.1084/jem.20060066
Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation.
Letimier Fabrice A,Passini Nadia,Gasparian Sona,Bianchi Elisabetta,Rogge Lars
The EMBO journal
Interleukin-12 (IL-12) is a key cytokine for the development of T helper type 1 (Th1) responses; however, naïve CD4(+) T cells do not express IL-12Rbeta2, and are therefore unresponsive to IL-12. We have examined the mechanisms that control Th1-specific expression of the human IL-12Rbeta2 gene at early time points after T-cell stimulation. We have identified a Th1-specific enhancer element that binds signal transducer and activator of transcription 4 (STAT4) in vivo in developing Th1 but not Th2 cells. T-cell receptor (TCR) signaling induced histone hyperacetylation and recruitment of BRG1, the ATPase subunit of the SWI/SNF-like BAF chromatin remodeling complex, to the IL-12Rbeta2 regulatory regions and was associated with low-level gene transcription at the IL-12Rbeta2 locus. However, high-level IL-12Rbeta2 expression required TCR triggering in the presence of IL-12. Our results indicate a synergistic role of TCR-induced chromatin remodeling and cytokine-induced STAT4 activation to direct IL-12Rbeta2 expression during Th1 cell development.
10.1038/sj.emboj.7601586
Molecular basis of CD4 repression by the Swi/Snf-like BAF chromatin remodeling complex.
Wan Mimi,Zhang Jianmin,Lai Dazhi,Jani Anant,Prestone-Hurlburt Paula,Zhao Lulu,Ramachandran Aruna,Schnitzler Gavin R,Chi Tian
European journal of immunology
The Brg1/Brm-associated factor (BAF) chromatin remodeling complex directly binds the CD4 silencer and is essential for CD4 repression during T-cell development, because deletion of the ATPase subunit Brg1 or a dominant negative mutant of BAF57 each impairs CD4 repression in early thymocytes. Paradoxically, BAF57 is dispensable for remodeling nucleosomes in vitro or for binding of the BAF complex to the CD4 silencer in vivo. Thus, it is unclear whether BAF57-dependent CD4 repression involves chromatin remodeling and, if so, how the remodeling translates into CD4 repression. Here we show that nucleosomes at the CD4 silencer occupy multiple translational frames. BAF57 dominant negative mutant does not alter these frames, but reduces the accessibility of the entire silencer without affecting the flanking regions, concomitant with localized accumulation of linker histone H1 and eviction of Runx1, a key repressor of CD4 transcription that directly binds the CD4 silencer. Our data indicate that precise nucleosome positioning is not critical for the CD4 silencer function and that BAF57 participates in remodeling H1-containing chromatin at the CD4 silencer, which enables Runx1 to access the silencer and repress CD4. In addition to BAF57, multiple other subunits in the BAF complex are also dispensable for chromatin remodelling in vitro. Our data suggest that these subunits could also help remodel chromatin at a step after the recruitment of the BAF complex to target genes.
10.1002/eji.200838909