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Glioma-associated oncogene homolog 1 (GLI1) is a core component of the Hedgehog (HH) signalling pathway and is a transcription activator of numerous oncogenes, such as SOX9, VEGFA, BCL2, and CDK2. The complex regulation of GLI1 involves numerous pathways and molecules, including HH-dependent and independent, epigenetic and post-transcriptional mechanisms. Here, we report the discovery, characterization and function of a novel sense promoter-associated ncRNA, paGLI1 that is overexpressed in infiltrating glioma. We show that paGLI1 promotes GLI1 gene transcription through binding to and recruitment of the transcription factor complex FUS/P65 by interacting with paGLI1 DNA sequence. This interaction facilitates FUS/P65 binding to the GLI1 promoter to activate GLI1 transcription and hence its downstream oncogenes, which results in enhancement of glioma cell proliferation and invasiveness. Importantly, over-expression of paGLI1 is a significant unfavorable prognosticator for both disease-specific and progression-free survival in glioma patients, with relative risks being 2.932 (95% confidence interval: 1.280 to 6.713) (P < 0.05) and 2.284 (95% confidence interval: 1.051 to 4.966) (P < 0.05), respectively. The novel paGLI1/FUS/P65 regulatory mechanisms play important roles in infiltrating glioma progression and may serve as potential targets for future therapeutics., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) have established chromosome 3p21.31 as a susceptibility locus for colorectal cancer (CRC) that lacks replication and exploration in the Chinese population. We searched potentially functional single nucleotide polymorphisms (SNPs) in the linkage disequilibrium (LD) block of 3p21.31 with chromatin immunoprecipitation-sequencing (ChIP-seq) data of histone modification, and tested their association with CRC via a case-control study involving 767 cases and 1397 controls in stage 1 and 528 cases and 678 controls in stage 2. In addition to the tag SNP rs8180040 (odds ratio (OR) = 0.875, 95% confidence interval (95% CI) = 0.793-0.966, P = 0.008, P-FDR (false discovery rate) = 0.040), rs1076394 presented consistently significant associations with CRC risk at both stages with OR = 0.850 (95% CI = 0.771-0.938, P = 0.001, P-FDR = 0.005) under the additive model in combined analyses. Supported by the analyses of data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), it was suggested that rs1076394 served as an expression Quantitative Trait Loci (eQTL) for gene CCDC12 and NME6, while NME6's expression was obviously higher in CRC tissues. Using biofeature information such as ChIP-seq and RNA sequencing (RNA-seq) data might help researchers to interpret GWAS results and locate functional variants for diseases in the post-GWAS era.

Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1int2, derived from intron 2 of FGFR1 gene, which is overexpressed in PCa and associated with tumor progression. Importantly, we show that circFGFR1int2 facilitates FGFR1 transcription by recruiting transcription activators P65/FUS and by interacting with FGFR1 promoter. Moreover, we show that circFGFR1int2 suppresses post-transcriptional inhibitory effects of miR-4687-5p on FGFR1 mRNA. These mechanisms synergistically promote PCa cell growth, migration, and invasion. Overexpression of circFGFR1int2 is significantly correlated with higher tumor grade, Gleason score, and PSA level, and is a significant unfavorable prognosticator for CRPC-free survival (CFS) (RR = 3.277, 95% confidence interval: 1.192–9.009; P = 0.021). These findings unravelled novel mechanisms controlling FGFR1 gene expression by intronic circRNA and its potential clinicopathological utility as a diagnostic or therapeutic target. [ABSTRACT FROM AUTHOR]

SUMMARY: DNA acetylation alters the expression of responsive genes during plant development. In grapes (Vitis vinifera), however, little is known about this regulatory mechanism. In the present study, 'Kyoho' grapes treated with trichostatin A (TSA, a deacetylase inhibitor) were used for transcriptome sequencing and quantitative proteomics analysis. We observed that acetylation was associated with anthocyanin accumulation and gene expression. Acetylation positively regulated phenylalanine metabolism and flavonoid biosynthesis pathways. Using omics analysis, we detected an increase in the levels of the AP2/EREBP transcription factor family after TSA treatment, indicating its association with acetylation–deacetylation dynamics in grapes. Furthermore, ethylene response factor 4 (ERF4) physically interacted with VvHDAC19, a histone deacetylase, which synergistically reduced the expression of target genes involved in anthocyanin biosynthesis owing to the binding of VvERF4 to the GCC‐box cis‐regulatory element in the VvMYB5a promoter. VvHDAC19 and VvERF4 also controlled anthocyanin biosynthesis and accumulation by regulating acetylation levels of histones H3 and H4. Therefore, alterations in histone modification can significantly regulate the expression of genes involved in anthocyanin biosynthesis and affect grape ripening. Significance Statement: The VvERF4–HDAC19 repressor complex downregulates MYB5a by binding to the GCC‐box motif in its promoter region, subsequently reducing anthocyanin accumulation in grapes (Vitis vinifera). [ABSTRACT FROM AUTHOR]

Simple Summary: The underlying mechanism of post-operative relapse of non-small cell lung cancer (NSCLC) remained poorly understood. This study highlights that both tumors and adjacent tissues from stage I NSCLC with relapse show a dysregulated immune and metabolic environment. Immune response shifts from an active state in primary tumors to a suppressive state in recurrent tumors. A model based on the enriched biological features in the primary tumors with relapse could effectively predict recurrence for stage I NSCLC. These results provide insights into the underpinning of the post-operative relapse and suggest that identifying NSCLC patients with a high risk of relapse could help the clinical decision of applying appropriate therapeutic interventions. The underlying mechanism of post-operative relapse of non-small cell lung cancer (NSCLC) remains poorly understood. We enrolled 57 stage I NSCLC patients with or without relapse and performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on available primary and recurrent tumors, as well as on matched tumor-adjacent tissues (TATs). The WES analysis revealed that primary tumors from patients with relapse were enriched with USH2A mutation and 2q31.1 amplification. RNA-seq data showed that the relapse risk was associated with aberrant immune response and metabolism in the microenvironment of primary lesions. TATs from the patients with relapse showed an immunosuppression state. Moreover, recurrent lesions exhibited downregulated immune response compared with their paired primary tumors. Genomic and transcriptomic features were further subjected to build a prediction model classifying patients into groups with different relapse risks. We show that the recurrence risk of stage I NSCLC could be ascribed to the altered immune and metabolic microenvironment. TATs might be affected by cancer cells and facilitate the invasion of tumors. The immune microenvironment in the recurrent lesions is suppressed. Patients with a high risk of relapse need active post-operative intervention. [ABSTRACT FROM AUTHOR]

37662RM1 and 37662RM2 are two phenotypically different, carbapenem-resistant mutants of Acinetobacter baumannii 37662 isolate following selection with meropenem (MEM) at sub-inhibitory concentrations. 37662RM2 lacks capsule synthesis and shows dramatically increased biofilm formation, while 37662RM1 shows merely impaired capsule synthesis. Here we report that 37662RM1 and RM2 have transcription profiles that are different from those of their starting strain, 37662WT. There were far more differentially expressed genes in 37662RM2 than in 37662RM1. The capsule polysaccharide (CPS) synthesis-required genes (itrA2 , gtr5 , psaA , psaB , psaC , psaD , psaE , psaF , kpsS2, wzx , wzy , wza , wzb , and wzc) showed reduced transcription levels in 37662RM2, which may at least partially explain the loss of capsule synthesis. The csu operon genes responsible for pili assembly and their regulator genes bfmR - bfmS were over-expressed in 37662RM2. This result together with the established critical roles of these genes in biofilm formation provide solid evidence that up-regulation of csu and bfmR - bfmS should be considered responsible for the enhanced biofilm formation in 37662RM2. IS Aba 1 was found to insert into the intergenic region between the csu operon and the acrR gene and should be responsible for the significant up-regulation of acrR , which was proposed to be associated with biofilm formation. Genome sequencing revealed that the IS Aba 1 upstream bla OXA–508 (a new member of bla OXA–51-like) and acrR were duplicated, suggesting a replicative transposition event. Altogether, the phenotype divergence driven by MEM selection mainly occurs at the RNA level and the transposition of IS Aba 1 plays an important role in modulating gene expression to adapt to the environment. [ABSTRACT FROM AUTHOR]

The SOX4 (sex-determining region Y-related high-mobility-group box transcription factor 4) gene plays critical roles in embryonic development and cell-fate determination. Recently, SOX4 overexpression has been found in various tumors. However, its expression status and prognostic significance in astrocytoma remain unknown. In this study, SOX4 expression in diffusely infiltrating astrocytoma ( WHO grades II-IV) tissues (in comparison with pilocytic astrocytomas) was examined by immunohistochemistry, and its relevance with prognosis was analyzed. Our data showed that SOX4 was over-expressed in diffusely infiltrating astrocytomas and its expression was positively correlated with astrocytoma grade ( WHO grades II-IV). Significantly, Kaplan- Meier analysis revealed that SOX4 nuclear overexpression ( SOX4- N) was associated with poorer progression-free survival ( PFS) and disease-specific survival ( DSS) in diffusely infiltrating astrocytoma patients ( P < 0.05). Cox regression analysis further showed that nuclear SOX4- N was a significant independent negative prognostic factor for these patients. [ABSTRACT FROM AUTHOR]

Summary: Malignant melanoma is characterized by apoptotic dysfunction, presumably due to abnormal expression of caspases and inhibitor of apoptosis proteins. However, the expression status and clinicopathologic significance of caspases and inhibitor of apoptosis proteins in cutaneous and particularly in mucosal melanomas have not been established. We investigated the expression of the major caspases (CASP3, 6, 7, 8, 9, and 10) and inhibitor of apoptosis proteins (survivin, CIAP1, CIAP2, XIAP, and Livin) by immunohistochemistry in 52 primary cutaneous and 25 mucosal melanomas, and 24 common nevi. Clinicopathologic and prognostic significance was investigated by statistical analysis. Our data showed that the significantly up-regulated inhibitor of apoptosis proteins in primary cutaneous and mucosal melanomas as compared with nevus (P < .01) were survivin, CIAP1, CIAP2, and Livin. Percentage of cases with positive caspase or IAP immunostaining was not significantly different between primary cutaneous and mucosal melanomas or between lower- and higher-stage melanomas (P > .05). Tumor location (cutaneous versus mucosal), stage, and positive cytoplasmic and nuclear survivin staining correlated significantly with prognosis by univariate analysis (P < .01). Multivariate analysis by Cox regression model showed that the most useful prognostic indicators were tumor location (cutaneous versus mucosal, relative risk = 6.021, 95% confidence interval = 2.623∼13.821, P = .000), stage (relative risk = 4.129, 95% confidence interval = 1.817∼9.383, P = .001), and nuclear survivin staining (relative risk = 3.383, 95% confidence interval = 1.137∼10.008, P = .028). [Copyright &y& Elsevier]

Abstract: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4+ T cells and especially CD8+ T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4+ and CD8+ T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-γ, TNF-α and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4+CD25+ regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4+CD25+ regulatory T cells. [Copyright &y& Elsevier]