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Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.
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Diferenciação Celular , Colite , Histona Desacetilases , Correpressor 1 de Receptor Nuclear , Células Th17 , Animais , Células Th17/citologia , Células Th17/metabolismo , Células Th17/imunologia , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Camundongos , Colite/genética , Colite/metabolismo , Colite/imunologia , Transcrição Gênica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Correpressor 2 de Receptor Nuclear/metabolismo , Correpressor 2 de Receptor Nuclear/genética , Interleucina-17/metabolismo , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , Humanos , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Interleucina-2/metabolismoRESUMO
Acetylation of histones by lysine acetyltransferases (KATs) provides a fundamental mechanism by which chromatin structure and transcriptional programs are regulated. Here, we describe a dual binding activity of the first winged helix domain of human MORF KAT (MORFWH1) that recognizes the TAZ2 domain of p300 KAT (p300TAZ2) and CpG rich DNA sequences. Structural and biochemical studies identified distinct DNA and p300TAZ2 binding sites, allowing MORFWH1 to independently engage either ligand. Genomic data show that MORF/MOZWH1 colocalizes with H3K18ac, a product of enzymatic activity of p300, on CpG rich promoters of target genes. Our findings suggest a functional cooperation of MORF and p300 KATs in transcriptional regulation.
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OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.
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Neoplasias , Neutrófilos , Masculino , Humanos , Feminino , Caquexia/etiologia , Estudos de Coortes , Força da Mão , Linfócitos , Prognóstico , Neoplasias/complicações , Estudos RetrospectivosRESUMO
Mucormycosis is receiving much more attention because of its high morbidity and extremely high mortality rate in immunosuppressed populations. In this study, we isolated a Cunnignhamella bertholletiae Z2 strain from a skin lesion of a 14â¯year, 9â¯months old girl with acute lymphoblastic leukemia who die of infection from the Z2 strain. Genome sequencing was performed after isolation and amplification of the Z2 strain to reveal potential virulence factors and pathogenic mechanisms. The results showed that the genome size of the Z2 strain is 30.9â¯Mb with 9213 genes. Mucoral specific virulence factor genes found are ARF, CalN, and CoTH, while no gliotoxin biosynthesis gene cluster was found, which is a known virulence factor in Aspergillus fumigatus adapted to the environment. The Z2 strain was found to have 69 cytochrome P450 enzymes, which are potential drug resistant targets. Sensitivity testing of Z2 showed it was only inhibited by amphotericin B and posaconazole. Detailed genomic information of the C. bertholletiae Z2 strain may provide useful data for treatment.
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Antifúngicos , Cunninghamella , Sistema Enzimático do Citocromo P-450 , Genoma Fúngico , Mucormicose , Sistema Enzimático do Citocromo P-450/genética , Mucormicose/microbiologia , Feminino , Humanos , Cunninghamella/genética , Antifúngicos/farmacologia , Adolescente , Fatores de Virulência/genética , Sequenciamento Completo do Genoma , Filogenia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMO
Site-specific histone modifications have long been recognized to play an important role in directing gene transcription in chromatin in biology of health and disease. However, concrete illustration of how different histone modifications in a site-specific manner dictate gene transcription outcomes, as postulated in the influential "Histone code hypothesis", introduced by Allis and colleagues in 2000, has been lacking. In this review, we summarize our latest understanding of the dynamic regulation of gene transcriptional activation, silence, and repression in chromatin that is directed distinctively by histone H3 lysine 27 acetylation, methylation, and crotonylation, respectively. This represents a special example of a long-anticipated verification of the "Histone code hypothesis."
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Histonas , Lisina , Transcrição Gênica , Acetilação , Cromatina/genética , Cromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Lisina/genética , Lisina/metabolismo , Ativação Transcricional , Domínios ProteicosRESUMO
Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.
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Cromatina , Histonas , Camundongos , Animais , Cromatina/genética , Histonas/metabolismo , Lisina/metabolismo , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica , AcetilaçãoRESUMO
The bromodomain acts to recognize acetylated lysine in histones and transcription proteins and plays a fundamental role in chromatin-based cellular processes including gene transcription and chromatin remodeling. Many bromodomain proteins, particularly the bromodomain and extra terminal domain (BET) protein BRD4 have been implicated in cancers and inflammatory disorders and recognized as attractive drug targets. Although clinical studies of many BET bromodomain inhibitors have made substantial progress toward harnessing the therapeutic potential of targeting the bromodomain proteins, the development of this new class of epigenetic drugs is met with challenges, especially on-target dose-limiting toxicity. In this review, we highlight the current development of new-generation small molecule inhibitors for the BET and non-BET bromodomain proteins and discuss the research strategies used to target different bromodomain proteins for a wide array of human diseases including cancers and inflammatory disorders.
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Neoplasias , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Histonas/metabolismo , Neoplasias/metabolismo , Cromatina , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/uso terapêuticoRESUMO
The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non-small cell lung cancer (NSCLC) patients treated with gefitinib. Combined treatment with dihydroartemisinin (DHA) and gefitinib produced a better inhibitory effect on lung adenocarcinoma than gefitinib treatment alone; however, the specific mechanism remains unclear. In this study, we aimed to assess the underlying mechanism of this combination treatment. We prepared gefitinib-resistant A549 cells and investigated whether apoptosis and ferroptosis were involved in the sensitizing effect of DHA. Treatment with 5 µM gefitinib resulted in rupturing and floatation of A549 cells in the medium, while A549-GR cells were found to be insusceptible to gefitinib. However, treatment with DHA substantially inhibited the proliferation of A549-GR cells in a dose-dependent manner accompanied by increased apoptosis and ferroptosis. The accumulated reactive oxygen species (ROS) was crucial for the inhibitory effect of DHA on A549-GR cells. Moreover, cellular autophagy was significantly upregulated post-DHA treatment. The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549-GR cells. DHA significantly induced apoptosis and ferroptosis in a dose-dependent manner and exhibited high cellular toxicity on A549-GR cells when combined with gefitinib.
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Adenocarcinoma de Pulmão , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Humanos , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio , Receptores ErbB/genética , Receptores ErbB/metabolismo , Quinazolinas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BRD4-NUT, a driver fusion mutant in rare and highly aggressive NUT carcinoma, acts in aberrant transcription of anti-differentiation genes by recruiting histone acetyltransferase (HAT) p300 and promoting p300-driven histone hyperacetylation and nuclear condensation in chromatin. However, the molecular basis of how BRD4-NUT recruits and activates p300 remains elusive. Here, we report that BRD4-NUT contains two transactivation domains (TADs) in NUT that bind to the TAZ2 domain in p300. Our NMR structures reveal that NUT TADs adopt amphipathic helices when bound to the four-helical bundle TAZ2 domain. The NUT protein forms liquid-like droplets in-vitro that are enhanced by TAZ2 binding in 1:2 stoichiometry. The TAD/TAZ2 bipartite binding in BRD4-NUT/p300 triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin that comprise histone H3 lysine 27 and 18 acetylation and transcription proteins BRD4L/S, CDK9, MED1, and RNA polymerase II. The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT's bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.
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Carcinoma , Proteínas de Ciclo Celular , Cromatina , Proteínas de Neoplasias , Proteínas Nucleares , Humanos , Acetilação , Carcinoma/metabolismo , Carcinoma/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteínas de Neoplasias/metabolismoRESUMO
BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.
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Proteínas Nucleares , Complexo Repressor Polycomb 2 , Camundongos , Animais , Complexo Repressor Polycomb 2/metabolismo , Proteínas Nucleares/metabolismo , Proteína 7 com Repetições F-Box-WD/metabolismo , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-5/metabolismo , Lisina , Diferenciação Celular/genética , Fatores de Transcrição Forkhead/genéticaRESUMO
Background: Despite the expanded immunization programs, the "re-emergence of pertussis" has become a global concern in recent years. At present, the prevalence of pertussis in China is seriously underestimated, and the role of close contact on the disease spreading in children remains unclear. Objectives: Our study aimed to investigate pertussis's epidemiological and clinical characteristics in children and their close contacts in households, as well as the antimicrobial resistance of Bordetella pertussis (B. pertussis) in Zhejiang Province, China. Methods: We have collected the retrospective and prospective data of children who were suspected of pertussis and their close contacts in households from January 1, 2018, to December 31, 2020, in the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Nasopharyngeal swabs were collected and cultured for B. pertussis. Antibiotics susceptibility test was determined by using E-test methods. Clinical information was collected from the medical records systems. Results: A total of 350 index patients and their 946 family members (close contacts in households) from 350 families were recruited. B. pertussis strains were isolated from 130 (37.1%) index patients and 116 (12.3%) close contacts. 37 index patients had negative culture results for B. pertussis while their close contacts were positive. A higher positive rate was found in female adults than that in male adults (16.3% vs. 5.1%, P < 0.01). The positive rate in index patients from multi-child families was significantly higher than that from one-child families (51.7% vs. 37.7%, P < 0.05). 53.3% of the pertussis patients were under 6 months of age. 98 (75.4%) isolates had MICs ≥ 256 mg/L to erythromycin, azithromycin, and clindamycin, and 127 (97.7%) had MICs < 0.016 mg/L to piperacillin. Conclusion: Infants under 6 months of age are at high risk of pertussis, and close contacts in households are prone to cluster infection. Culture for B. pertussis both in children and their close contacts contributes to improving the diagnosis rate of pertussis in children. Isolates of B. pertussis in China are highly resistant to macrolides.
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Nitryl cyanide, O2NCN, as a new high-energy molecule, has not yet been successfully synthesized. It has prompted us to conduct a theoretical study of its possible space structures and properties. The RESP charges and the most stable spatial structures demonstrate that crystal morphology is affected by both the main nonbonded interactions and the molecular arrangement. The crystal structure prediction indicated that there are seven structures, namely P1, P21, P212121, P21/c, Pna21, Pbca, and C2/c. The most stable space structure is likely to be Pna21 and the corresponding cell parameters are Z = 4, a = 8.69 Å, b = 9.07 Å, c = 9.65 Å, and α = ß = γ = 90.0°. To further study the intermolecular interactions of TNTA, a series of theoretical analyses were employed, including Hirshfeld surface analysis and fingerprint plots. The pyrolysis mechanism and properties show that high temperatures can promote decomposition. The systematic search approach can be a new strategy to identify structures effectively and has the potential to provide systematic theoretical guidance for the synthesis of TNTA.
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SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.
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Colite , Fator de Transcrição STAT3 , Animais , Diferenciação Celular/genética , Colite/genética , Colite/metabolismo , Ativação Linfocitária , Camundongos , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Th17RESUMO
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the unprecedented COVID-19 pandemic, which has infected over 178 million people worldwide. Even with new vaccines, global herd immunity will not be reached soon. New cases and viral variants are being reported at an alarming rate. Effective antiviral treatment is urgently needed. Patients with severe COVID-19 suffer from life-threatening respiratory failure due to acute respiratory distress syndrome in their lungs, a leading cause of COVID-19 mortality. This lung hyper-inflammation is induced by virus-caused massive tissue damage that is associated with uncontrolled cytokine release, known as a cytokine storm, through JAK/STAT signaling pathways. Here, we review the FDA-approved JAK inhibitors that are being clinically evaluated and repurposed for the treatment of patients with severe COVID-19 by calming SARS-CoV-2 infection.
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Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , HumanosRESUMO
BACKGROUND: Rodents are widely distributed and are the natural reservoirs of a diverse group of zoonotic viruses. Thus, analyzing the viral diversity harbored by rodents could assist efforts to predict and reduce the risk of future emergence of zoonotic viral diseases. Rodents are commonly used in animal testing, particularly mice and rats. Experimental rats are important animal models, and a history of pathogenic infections in these animals will directly affect the animal trial results. The pathogenicity of Anellovirus (AV) remains poorly understood due to the lack of a suitable model cell line or animal to support the viral cycle. This study aimed to discover possible anelloviruses from the virome in feces of experimental rats by viral metagenomic technique. METHODS: Fecal samples were collected from 10 commercial SD rats and pooled into a sample pool and then subjected to libraries construction which was then sequenced on Illumina MiSeq platform. The sequenced reads were analyzed using viral metagenomic analysis pipeline and two novel anelloviruses (AVs) were identified from fecal sample of experimental rats. The prevalence of these two viruses was investigated by conventional PCR. RESULTS: The complete genomic sequence of these two AVs were determined and fully characterized, with strain name ratane153-zj1 and ratane153-zj2. The circular genomes of ratane153-zj1 and ratane153-zj2 are 2785 nt and 1930 nt in length, respectively, and both include three ORFs. Ratane153-zj1 closely clustered with members within the genus Wawtorquevirus and formed a separate branch based on the phylogenetic tree constructed over the amino acid sequence of ORF1 of the two AVs identified in this study and other related AVs. While the complete amino acid sequences of ORF1 of ratane153-zj2 (nt 335 to 1390) had the highest sequence identity with an unclassified AV (GenBank No. ATY37438) from Chinchilla lanigera, and they clustered with one AV (GenBank No. QYD02305) belonging to the genus Etatorquevirus from Lynx rufus. Conventional PCR with two sets of specific primers designed based on the two genomes, respectively, showed that they were detectable at a low frequency in cohorts of experimental rats. CONCLUSION: Our study expanded the genome diversity of AVs and provided genetic background information of viruses existed in experimental rats.
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Anelloviridae , Animais , Fezes , Genoma Viral , Metagenômica/métodos , Camundongos , Filogenia , Ratos , Ratos Sprague-DawleyRESUMO
Staphylococcus aureus (S. aureus) is an important pathogen of ocular infections in pediatrics. The study aimed to identify the prevalence and resistance pattern of S. aureus, especially methicillin-resistant S. aureus (MRSA), in Chinese children with ocular infections. All patients with S. aureus infections were reviewed at a tertiary children's hospital during 2015-2020, and those with ocular infections were investigated for susceptibility results. Of 1,668 S. aureus strains, there were 177 unique isolates from ocular infection. Among them, 45 (25.4%) were MRSA and 132 (74.6%) were methicillin-sensitive S. aureus (MSSA). The proportion of MRSA did not change over time. Most of the strains were obtained from the neonate ward and ophthalmology department (n = 88, 49.7%, and n = 85, 48.0%, respectively), while eye secretion and pus were the main specimen types (n = 128, 72.3%, and n = 37, 20.9%, respectively). MRSA was significantly resistant against penicillin class (97.8%), erythromycin (71.1%), clindamycin (71.1%), and tetracycline (32.1%), with a high multidrug resistance (MDR) rate of 71.1%. However, MRSA was highly sensitive to levofloxacin. Resistance rates against erythromycin and ciprofloxacin as well as MDR percentage all increased among MSSA in children above 1 year of age, ophthalmology department, and outpatient population and decreased in eye secretion specimen. The mean resistance percentage remained stable for MRSA and MSSA during the study period. The survey of ocular S. aureus pathogens in pediatrics and their antibiotic resistance patterns helps in clinical treatment. MRSA with many strains demonstrating MDR is highly prevalent in children with ocular infections in Southeast China. Levofloxacin is an effective topical antibiotic for ocular MRSA infection, while erythromycin has a high resistance rate. The antibiotic resistance patterns of MRSA and MSSA differs and varies by different stratifications. A cautious use of antibiotics should be considered.
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The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins' functions in mediating protein-protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.
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STUDY OBJECTIVE: To study the bacteria and fungi causing vulvovaginitis in prepubertal girls. DESIGN: Swabs from vaginal introitus were collected from patients with vulvovaginitis in 2018, and cultured for the identification of microorganisms with standard microbiological techniques. SETTING: A children's hospital in Hangzhou, East China. PARTICIPANTS: A total of 1235 Chinese prepubertal girls diagnosed with vulvovaginitis. MAIN OUTCOME MEASURE: Bacteria or fungi in pure cultures or as the predominant organism were defined as pathogens. RESULTS: A total of 1235 cases were diagnosed as vulvovaginitis, and 515 isolates were identified from 494 patients (40%, 494/1235). The most common pathogen was Streptococcus pyogenes (27.6%,142/515), followed by Haemophilus influenzae (27.2%,140/515), Candida albicans (22.3%,115/515), Staphylococcus aureus (5.8%, 30/515) and Escherichia coli (4.7%,24/515). All S pyogenes isolates were sensitive to penicillin, whereas 53.7% (73/136) of H influenzae isolates were sensitive to ampicillin, and 70.4% (19/27) of S aureus isolates were sensitive to oxacillin. CONCLUSION: S pyogenes and H influenzae were the 2 most commonly identified pathogenic bacteria found in prepubertal girls with vulvovaginitis. Vulvovaginitis in prepubertal girls caused by C albicans may be more common in older children.
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Vulvovaginite , Criança , China/epidemiologia , Feminino , Haemophilus influenzae , Humanos , Streptococcus pyogenesRESUMO
In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.
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Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Viroses/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Nucleares/deficiência , Ligação Proteica , Interferência de RNA , Fatores de Transcrição/deficiência , Transcrição GênicaRESUMO
Spindlin1 is a unique multivalent epigenetic reader that facilitates ribosomal RNA transcription. In this study, we provide molecular and structural basis by which Spindlin1 acts in complex with C11orf84 to preferentially recognize non-canonical bivalent mark of trimethylated lysine 4 and lysine 9 present on the same histone H3 tail (H3K4me3K9me3). We demonstrate that C11orf84 binding stabilizes Spindlin1 and enhances its association with bivalent H3K4me3K9me3 mark. The functional analysis suggests that Spindlin1/C11orf84 complex can displace HP1 proteins from H3K4me3K9me3-enriched rDNA loci, thereby facilitating the conversion of these poised rDNA repeats from the repressed state to the active conformation, and the consequent recruitment of RNA Polymerase I for rRNA transcription. Our study uncovers a previously unappreciated mechanism of bivalent H3K4me3K9me3 recognition by Spindlin1/C11orf84 complex required for activation of rRNA transcription.