General transcription factor from Escherichia coli with a distinct mechanism of action.

Gene expression in Escherichia coli is controlled by well-established mechanisms that activate or repress transcription. Here, we identify CedA as an unconventional transcription factor specifically associated with the RNA polymerase (RNAP) σ70 holoenzyme. Structural and biochemical analysis of CedA bound to RNAP reveal that it bridges distant domains of ß and σ70 subunits to stabilize an open-promoter complex. CedA does so without contacting DNA. We further show that cedA is strongly induced in response to amino acid starvation, oxidative stress and aminoglycosides. CedA provides a basal level of tolerance to these clinically relevant antibiotics, as well as to rifampicin and peroxide. Finally, we show that CedA modulates transcription of hundreds of bacterial genes, which explains its pleotropic effect on cell physiology and pathogenesis.

Neurodevelopmental and other phenotypes recurrently associated with heterozygous BAZ2B loss-of-function variants.

The bromodomain adjacent to zinc finger 2B (BAZ2B) gene encodes a chromatin remodeling protein that has been shown to perform a variety of regulatory functions. It has been proposed that loss of BAZ2B function is associated with neurodevelopmental phenotypes, and some recurrent structural birth defects and dysmorphic features have been documented among individuals carrying heterozygous loss-of-function BAZ2B variants. However, additional evidence is needed to confirm that these phenotypes are attributable to BAZ2B deficiency. Here, we report 10 unrelated individuals with heterozygous deletions, stop-gain, frameshift, missense, splice junction, indel, and start-loss variants affecting BAZ2B. These included a paternal intragenic deletion and a maternal frameshift variant that were inherited from mildly affected or asymptomatic parents. The analysis of molecular and clinical data from this cohort, and that of individuals previously reported, suggests that BAZ2B haploinsufficiency causes an autosomal dominant neurodevelopmental syndrome that is incompletely penetrant. The phenotypes most commonly seen in association with loss of BAZ2B function include developmental delay, intellectual disability, autism spectrum disorder, speech delay-with some affected individuals being non-verbal-behavioral abnormalities, seizures, vision-related issues, congenital heart defects, poor fetal growth, and an indistinct pattern of dysmorphic features in which epicanthal folds and small ears are particularly common.

Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer.

OBJECTIVE: Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression; however, the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive. It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets. METHODS: We employed high-throughput sequencing-based high-throughput screening (HTS2) to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators. Then, bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer. RESULTS: Utilizing these gene expression signatures, we classified the epigenetic regulators into five distinct clusters, each characterized by specific functions. We discovered functional similarities between BAZ2B and SETMAR, as well as CLOCK and CBX3. Moreover, we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation. Notably, we constructed an epigenetic regulatory network based on the gene expression signatures, which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer. CONCLUSIONS: Our work deciphered the extensive regulation among hundreds of epigenetic regulators. The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

baz-2 enhances systemic proteostasis in vivo by regulating acetylcholine metabolism.

Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic hypothesis," loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegans ortholog of human BAZ2B, limits ACh signaling. baz-2 mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2 is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2 reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.

Structural visualization of transcription initiation in action.

Transcription initiation is a complex process, and its mechanism is incompletely understood. We determined the structures of de novo transcribing complexes TC2 to TC17 with RNA polymerase II halted on G-less promoters when nascent RNAs reach 2 to 17 nucleotides in length, respectively. Connecting these structures generated a movie and a working model. As initially synthesized RNA grows, general transcription factors (GTFs) remain bound to the promoter and the transcription bubble expands. Nucleoside triphosphate (NTP)-driven RNA-DNA translocation and template-strand accumulation in a nearly sealed channel may promote the transition from initially transcribing complexes (ITCs) (TC2 to TC9) to early elongation complexes (EECs) (TC10 to TC17). Our study shows dynamic processes of transcription initiation and reveals why ITCs require GTFs and bubble expansion for initial RNA synthesis, whereas EECs need GTF dissociation from the promoter and bubble collapse for promoter escape.

Fake IDs? Widespread misannotation of DNA transposons as a general transcription factor.

Accurate annotation of genes and transposable elements (TEs) is vital for understanding genomes, but current annotation pipelines often misannotate TEs as genes. This study reveals how the general transcription factor II-I repeat domain-containing protein 2 (GTF2IRD2) erroneously annotated DNA transposons in non-mammalian species, as it contains a 3' fused hAT transposase domain. We also demonstrate the generality of this problem by identifying misannotated TEs as genes in other vertebrate genomes. Such misannotations can lead to errors in phylogenetic analyses and wasted time for investigators. The study proposes adding a final TE-check to gene annotation pipelines to mitigate this problem.

The Conserved Chromatin Remodeler SMARCAD1 Interacts with TFIIIC and Architectural Proteins in Human and Mouse.

In vertebrates, SMARCAD1 participates in transcriptional regulation, heterochromatin maintenance, DNA repair, and replication. The molecular basis underlying its involvement in these processes is not well understood. We identified the RNA polymerase III general transcription factor TFIIIC as an interaction partner of native SMARCAD1 in mouse and human models using endogenous co-immunoprecipitations. TFIIIC has dual functionality, acting as a general transcription factor and as a genome organizer separating chromatin domains. We found that its partnership with SMARCAD1 is conserved across different mammalian cell types, from somatic to pluripotent cells. Using purified proteins, we confirmed that their interaction is direct. A gene expression analysis suggested that SMARCAD1 is dispensable for TFIIIC function as an RNA polymerase III transcription factor in mouse ESCs. The distribution of TFIIIC and SMARCAD1 in the ESC genome is distinct, and unlike in yeast, SMARCAD1 is not enriched at active tRNA genes. Further analysis of SMARCAD1-binding partners in pluripotent and differentiated mammalian cells reveals that SMARCAD1 associates with several factors that have key regulatory roles in chromatin organization, such as cohesin, laminB, and DDX5. Together, our work suggests for the first time that the SMARCAD1 enzyme participates in genome organization in mammalian nuclei through interactions with architectural proteins.

Reevaluation of bromodomain ligands targeting BAZ2A.

BAZ2A promotes migration and invasion in prostate cancer. Two chemical probes, the specific BAZ2-ICR, and the BAZ2/BRD9 cross-reactive GSK2801, interfere with the recognition of acetylated lysines in histones by the bromodomains of BAZ2A and of its BAZ2B paralog. The two chemical probes were tested in prostate cancer cell lines with opposite androgen susceptibility. BAZ2-ICR and GSK2801 showed different cellular efficacies in accordance with their unequal selectivity profiles. Concurrent inhibition of BAZ2 and BRD9 did not reproduce the effects observed with GSK2801, indicating possible off-targets for this chemical probe. On the other hand, the single BAZ2 inhibition by BAZ2-ICR did not phenocopy genetic ablation, demonstrating that bromodomain interference is not sufficient to strongly affect BAZ2A functionality and suggesting a PROTAC-based chemical ablation as an alternative optimization strategy and a possible therapeutic approach. In this context, we also present the crystallographic structures of BAZ2A in complex with the above chemical probes. Binding poses of TP-238 and GSK4027, chemical probes for the bromodomain subfamily I, and two ligands of the CBP/EP300 bromodomains identify additional headgroups for the development of BAZ2A ligands.

RNA polymerase II associates with active genes during DNA replication.

The transcriptional machinery is thought to dissociate from DNA during replication. Certain proteins, termed epigenetic marks, must be transferred from parent to daughter DNA strands in order to maintain the memory of transcriptional states1,2. These proteins are believed to re-initiate rebuilding of chromatin structure, which ultimately recruits RNA polymerase II (Pol II) to the newly replicated daughter strands. It is believed that Pol II is recruited back to active genes only after chromatin is rebuilt3,4. However, there is little experimental evidence addressing the central questions of when and how Pol II is recruited back to the daughter strands and resumes transcription. Here we show that immediately after passage of the replication fork, Pol II in complex with other general transcription proteins and immature RNA re-associates with active genes on both leading and lagging strands of nascent DNA, and rapidly resumes transcription. This suggests that the transcriptionally active Pol II complex is retained in close proximity to DNA, with a Pol II-PCNA interaction potentially underlying this retention. These findings indicate that the Pol II machinery may not require epigenetic marks to be recruited to the newly synthesized DNA during the transition from DNA replication to resumption of transcription.

Promoter-proximal regulation of gene transcription: Key factors involved and emerging role of general transcription factors in assisting productive elongation.

The pausing of RNA polymerase II (Pol II) at the promoter-proximal sites is a key rate-limiting step in gene expression. Cells have dedicated a specific set of proteins that sequentially establish pause and then release the Pol II from promoter-proximal sites. A well-controlled pausing and subsequent release of Pol II is crucial for the fine tuning of expression of genes including signal-responsive and developmentally-regulated ones. The release of paused Pol II broadly involves its transition from initiation to elongation. In this review article, we will discuss the phenomenon of Pol II pausing, the underlying mechanism, and also the role of different known factors, with an emphasis on general transcription factors, involved in this overall regulation. We will further discuss some recent findings suggesting a possible role (underexplored) of initiation factors in assisting the transition of transcriptionally-engaged paused Pol II into productive elongation.

GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation.

Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in tumors without known genetic aberrations or those which are unresponsive to other treatments. Unfortunately, resistance often develops and, for this reason, new therapies that overcome taxane resistance are needed. In this study, effects of inhibition of several bromodomain proteins in paclitaxel-resistant ATC cell lines were investigated. GSK2801, a specific inhibitor of BAZ2A, BAZ2B and BRD9, was effective in resensitizing cells to paclitaxel. In fact, when used in combination with paclitaxel, it was able to reduce cell viability, block the ability to form colonies in an anchor-independent manner, and strongly decrease cell motility. After RNA-seq following treatment with GSK2801, we focused our attention on MYCN. Based on the hypothesis that MYCN was a major downstream player in the biological effects of GSK2801, we tested a specific inhibitor, VPC-70619, which showed effective biological effects when used in association with paclitaxel. This suggests that the functional deficiency of MYCN determines a partial resensitization of the cells examined and, ultimately, that a substantial part of the effect of GSK2801 results from inhibition of MYCN expression.

Targeting G-quadruplexes in an ageing epigenetic regulator promoter for rescuing mitochondrial dysfunction in Alzheimer's disease.

Here, we provide an out-of-the-box G-quadruplex (G4) targeting-based strategy for rescuing mitochondrial dysfunction in Alzheimer's disease. We predict and verify the presence of G4s within the promoter of an ageing epigenetic regulator BAZ2B. G4-specific ligands targeting BAZ2B G4s could significantly down-regulate the BAZ2B expression and relieve mitochondrial dysfunction. Therefore, this work may provide a new way of rescuing mitochondrial dysfunction in AD by targeting G4s in a specific ageing epigenetic regulator promoter.

Coordinated regulation of plant defense and autoimmunity by paired trihelix transcription factors ASR3/AITF1 in Arabidopsis.

Plants perceive pathogens and induce robust transcriptional reprogramming to rapidly achieve immunity. The mechanisms of how immune-related genes are transcriptionally regulated remain largely unknown. Previously, the trihelix transcriptional factor ARABIDOPSIS SH4-RELATED 3 (ASR3) was shown to negatively regulate pattern-triggered immunity (PTI) in Arabidopsis thaliana. Here, we identified another trihelix family member ASR3-Interacting Transcriptional Factor 1 (AITF1) as an interacting protein of ASR3. ASR3-Interacting Transcriptional Factor 1 and ASR3 form heterogenous and homogenous dimers in planta. Both aitf1 and asr3 single mutants exhibited increased resistance against the bacterial pathogen Pseudomonas syringae, but the double mutant showed reduced resistance, suggesting AITF1 and ASR3 interdependently regulate immune gene expression and resistance. Overexpression of AITF1 triggered autoimmunity dependently on its DNA-binding ability and the presence of ASR3. Notably, autoimmunity caused by overexpression of AITF1 was dependent on a TIR-NBS-LRR (TNL) protein suppressor of AITF1-induced autoimmunity 1 (SAA1), as well as enhanced disease susceptibility 1 (EDS1), the central regulator of TNL signaling. ASR3-Interacting Transcriptional Factor 1 and ASR3 directly activated SAA1 expression through binding to the GT-boxes in SAA1 promoter. Collectively, our results revealed a mechanism of trihelix transcription factor complex in regulating immune gene expression, thereby modulating plant disease resistance and autoimmunity.

Enhancement of Vivid-based photo-activatable Gal4 transcription factor in mammalian cells.

The Gal4/UAS system is a versatile tool to manipulate exogenous gene expression of cells spatially and temporally in many model organisms. Many variations of light-controllable Gal4/UAS system are now available, following the development of photo-activatable (PA) molecular switches and integration of these tools. However, many PA-Gal4 transcription factors have undesired background transcription activities even in dark conditions, and this severely attenuates reliable light-controlled gene expression. Therefore, it is important to develop reliable PA-Gal4 transcription factors with robust light-induced gene expression and limited background activity. By optimization of synthetic PA-Gal4 transcription factors, we have validated configurations of Gal4 DNA biding domain, transcription activation domain and blue light-dependent dimer formation molecule Vivid (VVD), and applied types of transcription activation domains to develop a new PA-Gal4 transcription factor we have named eGAV (enhanced Gal4-VVD transcription factor). Background activity of eGAV in dark conditions was significantly lower than that of hGAVPO, a commonly used PA-Gal4 transcription factor, and maximum light-induced gene expression levels were also improved. Light-controlled gene expression was verified in cultured HEK293T cells with plasmid-transient transfections, and in mouse EpH4 cells with lentivirus vector-mediated transduction. Furthermore, light-controlled eGAV-mediated transcription was confirmed in transfected neural stem cells and progenitors in developing and adult mouse brain and chick spinal cord, and in adult mouse hepatocytes, demonstrating that eGAV can be applied to a wide range of experimental systems and model organisms.Key words: optogenetics, Gal4/UAS system, transcription, gene expression, Vivid.

Transtornos alimentares: vivências de mulheres acima de 30 anos / Eating disorders: experiences of women aged over 30 years / Trastornos alimentarios: experiencias de mujeres de más de 30 años

O objetivo deste estudo foi compreender como mulheres adultas (acima de 30 anos) diagnosticadas com transtornos alimentares (TAs) vivenciam o adoecer. Trata-se de um estudo qualitativo, descritivo e exploratório, desenvolvido com base no referencial teórico-metodológico da Análise Fenomenológica Interpretativa (AFI). Participaram seis mulheres, com idades entre 34 e 65 anos, atendidas em um serviço especializado. Os dados foram coletados por meio de entrevista aberta, de inspiração fenomenológica, na modalidade remota. As entrevistas foram audiogravadas, transcritas e analisadas seguindo os passos da AFI. Duas categorias temáticas foram identificadas: "Vivendo antes do adoecer" e "Encontrando-se doente." Constatou-se que os sintomas tiveram início anteriormente à vida adulta e que houve dificuldade na confirmação do diagnóstico. Na perspectiva das participantes, conviver com a sintomatologia ficou mais complicado em função de particularidades de manejo dos sintomas na vida adulta, e a idade é percebida como um fator que impacta e dificulta ainda mais a recuperação. As participantes relataram desesperança em relação ao futuro, apesar de a maioria reconhecer melhoras no quadro clínico ao longo do tempo e de valorizar a relação de confiança estabelecida com a equipe multiprofissional.(AU)

This study aimed to understand the experience of illness of adult women (over 30 years) diagnosed with eating disorders (ED). This is a qualitative, descriptive, and exploratory study, using Interpretative Phenomenological Analysis (IPA) as theoretical and methodological framework. A sample of six women aged 34-64 years, assisted in a specialized service, were recruited to complete a phenomenological in-depth open interview. The data were remotely collected. Interviews were audio-recorded, transcribed and analyzed following the IPA. Two thematic categories were identified: "Living before the illness" and "Finding about the illness." It was found that the symptoms started before adulthood and that there was difficulty establishing the diagnosis. Living with the symptoms became more complicated due to particularities of symptom management in adulthood and age is perceived as a factor that impacts recovery and makes it even more difficult. The participants reported hopelessness about the future, although most recognized improvements in the clinical condition over time and valued the trusting relationship they established with the multiprofessional team.(AU)

El objetivo de este estudio fue comprender las experiencias de las mujeres adultas (mayores de 30 años) diagnosticadas con trastornos alimentarios (TA) respecto a la enfermedad. Se trata de un estudio cualitativo, descriptivo y exploratorio, desarrollado a partir del marco teórico y metodológico del Análisis Fenomenológico Interpretativo (AFI). Participaron seis mujeres, con edades de entre 34 y 65 años, atendidas en un servicio especializado. Los datos se recogieron mediante entrevistas abiertas, de inspiración fenomenológica, en la modalidad a distancia. Las entrevistas fueron grabadas en audio, transcritas y analizadas siguiendo los pasos del AFI. Se identificaron dos categorías temáticas: "Vivir antes de enfermar" y "Encontrarse enfermo." Se constató que los síntomas comenzaron antes de la edad adulta y que hubo dificultades de establecer el diagnóstico. La convivencia con síntomas se complicó debido a las particularidades del manejo de los síntomas en la vida adulta y la edad se percibe como un factor que influye y dificulta aún más la recuperación. Los participantes manifestaron desesperanza sobre el futuro, aunque reconocieron mejoras en el cuadro clínico con el paso del tiempo y valoraron la relación de confianza establecida con el equipo multiprofesional.(AU)

A remodeled RNA polymerase II complex catalyzing viroid RNA-templated transcription.

Viroids, a fascinating group of plant pathogens, are subviral agents composed of single-stranded circular noncoding RNAs. It is well-known that nuclear-replicating viroids exploit host DNA-dependent RNA polymerase II (Pol II) activity for transcription from circular RNA genome to minus-strand intermediates, a classic example illustrating the intrinsic RNA-dependent RNA polymerase activity of Pol II. The mechanism for Pol II to accept single-stranded RNAs as templates remains poorly understood. Here, we reconstituted a robust in vitro transcription system and demonstrated that Pol II also accepts minus-strand viroid RNA template to generate plus-strand RNAs. Further, we purified the Pol II complex on RNA templates for nano-liquid chromatography-tandem mass spectrometry analysis and identified a remodeled Pol II missing Rpb4, Rpb5, Rpb6, Rpb7, and Rpb9, contrasting to the canonical 12-subunit Pol II or the 10-subunit Pol II core on DNA templates. Interestingly, the absence of Rpb9, which is responsible for Pol II fidelity, explains the higher mutation rate of viroids in comparison to cellular transcripts. This remodeled Pol II is active for transcription with the aid of TFIIIA-7ZF and appears not to require other canonical general transcription factors (such as TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and TFIIS), suggesting a distinct mechanism/machinery for viroid RNA-templated transcription. Transcription elongation factors, such as FACT complex, PAF1 complex, and SPT6, were also absent in the reconstituted transcription complex. Further analyses of the critical zinc finger domains in TFIIIA-7ZF revealed the first three zinc finger domains pivotal for RNA template binding. Collectively, our data illustrated a distinct organization of Pol II complex on viroid RNA templates, providing new insights into viroid replication, the evolution of transcription machinery, as well as the mechanism of RNA-templated transcription.

Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.

Few human tumours present with a recurrent pathognomonic mutation in a transcription factor. Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I. Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity. Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation of bi-potent epithelial progenitors. The resulting gene expression signature is dominated by that of immature cortex-like thymic epithelial cells. TCR repertoire analysis of the cytopenic T cell compartment indicates efficient intrathymic selection; hence, despite marked homeostatic proliferation of T cell clones, autoimmunity is not observed. Thus, our transgenic mouse model recapitulates some aspects of the pathophysiology of a genetically defined type of human thymoma.

A New Long Noncoding RNA, MAHAT, Inhibits Replication of Porcine Reproductive and Respiratory Syndrome Virus by Recruiting DDX6 To Bind to ZNF34 and Promote an Innate Immune Response.

Long noncoding RNAs (lncRNAs) have increasingly been recognized as being integral to cellular processes, including the antiviral immune response. Porcine reproductive and respiratory syndrome virus (PRRSV) is costly to the global swine industry. To identify PRRSV-related lncRNAs, we performed RNA deep sequencing and compared the profiles of lncRNAs in PRRSV-infected and uninfected Marc-145 cells. We identified a novel lncRNA called MAHAT (maintaining cell morphology-associated and highly conserved antiviral transcript; LTCON_00080558) that inhibits PRRSV replication. MAHAT binds and negatively regulates ZNF34 expression by recruiting and binding DDX6, an RNA helicase forming a complex with ZNF34. Inhibition of ZNF34 expression results in increased type I interferon expression and decreased PRRSV replication. This finding reveals a novel mechanism by which PRRSV evades the host antiviral innate immune response by downregulating the MAHAT-DDX6-ZNF34 pathway. MAHAT could be a host factor target for antiviral therapies against PRRSV infection. IMPORTANCE Long noncoding RNAs (lncRNAs) play important roles in viral infection by regulating the transcription and expression of host genes, and interferon signaling pathways. Porcine reproductive and respiratory syndrome virus (PRRSV) causes huge economic losses in the swine industry worldwide, but the mechanisms of its pathogenesis and immunology are not fully understood. Here, a new lncRNA, designated MAHAT, was identified as a regulator of host innate immune responses. MAHAT negatively regulates the expression of its target gene, ZNF34, by recruiting and binding DDX6, an RNA helicase, forming a complex with ZNF34. Inhibition of ZNF34 expression increases type I interferon expression and decreases PRRSV replication. This finding suggests that MAHAT has potential as a new target for developing antiviral drugs against PRRSV infection.

Thymic epithelial tumors: examining the GTF2I mutation and developing a novel prognostic signature with LncRNA pairs to predict tumor recurrence.

BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

Myelin oligodendrocyte glycoprotein-associated disease is associated with BANK1, RNASET2 and TNIP1 polymorphisms.

AIM: Here we aimed to compare association of common immune-related genetic variants with three autoimmune central nervous system (CNS) demyelinating diseases, namely myelin oligodendrocyte glycoprotein-associated disease (MOGAD), multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this retrospective cross-sectional study, 26 common immune-related single nucleotide polymorphisms were genotyped in 102 patients with MOGAD, 100 patients with MS, 198 patients with NMOSD and 541 healthy control subjects recruited from Guangzhou, China. RESULTS: Among all tested genetic variations, one polymorphism, B cell scaffold protein with ankyrin repeats 1 (BANK1) rs4522865 was associated with multiple disorders, namely MOGAD (OR = 1.94, 95% CI:1.19-3.17, P = 0.0059) and NMOSD (OR = 1.69, 95% CI:1.17-2.45). Besides BANK1 rs4522865, two other non-HLA loci, ribonuclease T2 (RNASET2) rs9355610 (OR = 0.47, 95% CI: 0.26-0.85) and TNFAIP3 interacting protein 1 (TNIP1) rs10036748 (OR = 1.76, 95% CI: 1.16-2.71), were associated with MOGAD. In addition, NMOSD was associated with signal transducer and activator of transcription 4 (STAT4) rs7574865 (OR = 1.58, 95% CI: 1.12-2.24) and general transcription factor Iii (GTF2I) rs73366469 (OR = 1.60, 95% CI:1.12-2.29), while MS was associated with a killer cell lectin like receptor G1 (KLRG1) rs1805673 (OR = 0.61, 95% CI: 0.40-0.94) and T-box transcription factor 21 (TBX21) rs17244587 (OR = 2.25, 95% CI: 1.25-4.06). CONCLUSION: The current study suggests for the first time three non-HLA susceptibility loci for MOGAD. In addition, comparison of association of 26 immune-related polymorphisms with three autoimmune CNS demyelinating diseases demonstrates substantial difference in genetic basis of those disorders.