Pan-cancer analysis on microRNA-mediated gene activation

2018 ◽  
Author(s):  
Hua Tan ◽  
Shan Huang ◽  
Zhigang Zhang ◽  
Xiaohua Qian ◽  
Peiqing Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Immune Cell ◽  
Critical Role ◽  
Mirna Gene ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Positive Correlation ◽  
Positive Correlations

ABSTRACTWhile microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Results indicated that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate, demonstrating their promising clinical relevance. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs, suggesting a potential epigenetics mechanism underlying the upregulation. Wet-lab experiments revealed that positive correlations partially remain in the in vitro condition. Our study provides the field with new perspectives on the critical role of miRNA in gene regulation and novel insights regarding the complex mechanisms underlying miRNA functions, and reveals the clinical significance of the potential positive regulation of gene expression by miRNA.

Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 25-25
Author(s):  
Yuanyuan Shen ◽  
Justin Hummel ◽  
Isabel Cristina Trindade ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Epigenetic Modification ◽  
Pearson Correlation ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Highly Correlated

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.

scholarly journals Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingyi Chen ◽  
Yuxuan Song ◽  
Mei Li ◽  
Yu Zhang ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Target Genes ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

scholarly journals Time-Course Transcriptome Study Reveals Mode of bZIP Transcription Factors on Light Exposure in Arabidopsis

2020 ◽  
Vol 21 (6) ◽  
pp. 1993 ◽  
Author(s):  
Yukio Kurihara ◽  
Yuko Makita ◽  
Haruka Shimohira ◽  
Minami Matsui
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Target Genes ◽  
Light Exposure ◽  
Expression Profiles ◽  
Red Light ◽  
Monochromatic Light ◽  
Regulation Of Gene Expression ◽  
Light Irradiation

The etiolation process, which occurs after germination, is terminated once light is perceived and then de-etiolation commences. During the de-etiolation period, monochromatic lights (blue, red and far-red) induce differences in gene expression profiles and plant behavior through their respective photoreceptors. ELONGATED HYPOCOTYL 5 (HY5), a bZIP-type transcription factor (TF), regulates gene expression in the de-etiolation process, and other bZIP TFs are also involved in this regulation. However, transcriptomic changes that occur in etiolated seedlings upon monochromatic light irradiation and the relationship with the bZIP TFs still remain to be elucidated. Here, we track changes in the transcriptome after exposure to white, blue, red and far-red light following darkness and reveal both shared and non-shared trends of transcriptomic change between the four kinds of light. Interestingly, after exposure to light, HY5 expression synchronized with those of the related bZIP TF genes, GBF2 and GBF3, rather than HY5 HOMOLOG (HYH). To speculate on the redundancy of target genes between the bZIP TFs, we inspected the genome-wide physical binding sites of homodimers of seven bZIP TFs, HY5, HYH, GBF1, GBF2, GBF3, GBF4 and EEL, using an in vitro binding assay. The results reveal large overlaps of target gene candidates, indicating a complicated regulatory literature among TFs. This work provides novel insight into understanding the regulation of gene expression of the plant response to monochromatic light irradiation.

scholarly journals Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

2005 ◽  
Vol 25 (15) ◽  
pp. 6592-6602 ◽  
Author(s):  
Wei-Chien Huang ◽  
Ching-Chow Chen
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Histone Acetyltransferase ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Necrosis Factor Alpha ◽  
Akt Phosphorylation ◽  
Basal Transcriptional Machinery

ABSTRACT The PI3K/Akt pathway plays a critical role in the regulation of gene expression induced by numerous stimuli. p300, a transcriptional coactivator, acts in concert with transcription factors to facilitate gene expression. Here, we show that Akt is activated and translocated to the nucleus in response to tumor necrosis factor alpha. Nuclear Akt associates with p300 and phosphorylates its Ser-1834 both in vivo and in vitro. The phosphorylation induces recruitment of p300 to the ICAM-1 promoter, leading to the acetylation of histones in chromatin and association with the basal transcriptional machinery RNA polymerase II. These two events facilitate ICAM-1 gene expression and are abolished by the p300 S1834A mutant, inhibitors of PI3K/Akt, or small interfering RNA of Akt. Histone acetylation is attributed to the Akt-enhanced intrinsic histone acetyltransferase (HAT) activity of p300 and its association with another HAT, p/CAF. Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300.

scholarly journals Enhanced SMARCD1, a subunit of the SWI/SNF complex, promotes liver cancer growth through the mTOR pathway

2020 ◽  
Vol 134 (12) ◽  
pp. 1457-1472
Author(s):  
Yongjie Zhou ◽  
Qing Xu ◽  
Lv Tao ◽  
Yuwei Chen ◽  
Yuke Shu ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Target Genes ◽  
Critical Role ◽  
Clinical Information ◽  
Normal Liver ◽  
The Cancer Genome Atlas ◽  
Cancer Growth ◽  
Interaction Domain

Abstract The chromatin remodeling complex SWI/SNF regulates the accessibility of target genes to transcription factors and plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). The SWI/SNF complex is assembled from approximately 15 subunits, and most of these subunits have distinct roles and are often aberrantly expressed in HCC. A comprehensive exploration of the expression and clinical significance of these subunits would be of great value. In the present study, we obtained the gene expression profile of each SWI/SNF subunit and the corresponding clinical information from The Cancer Genome Atlas (TCGA). We found that 14 out of the 15 SWI/SNF subunits were significantly increased in HCC tissues compared with paired normal liver tissues, and 11 subunits were significantly associated with overall survival (OS). We identified a four-gene prognostic signature including actin-like 6A (ACTL6A), AT-rich interaction domain 1A (ARID1A), SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 1 (SMARCC1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1 (SMARCD1) that could effectively predict OS in HCC patients. Among the genes, SMARCD1 has the most prognostic value. We further conducted in vitro and in vivo experiments and revealed that SMARCD1 promotes liver cancer growth by activating the mTOR signaling pathway. In conclusion, our study has revealed that the expression of SWI/SNF complex subunits, especially SMARCD1, is highly associated with HCC development and acts as a promising prognostic predictor.

scholarly journals Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

2010 ◽  
Vol 17 (3) ◽  
pp. 809-822 ◽  
Author(s):  
Louise Maymann Rasmussen ◽  
Klaus Stensgaard Frederiksen ◽  
Nanni Din ◽  
Elisabeth Galsgaard ◽  
Leif Christensen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Pituitary Hormone

The pituitary hormone prolactin (PRL) plays an important role in mammary gland development. It was also suggested to contribute to breast cancer progression. In vivo data strongly supported a crucial role of PRL in promoting tumour growth; however, PRL demonstrated only a weak, if any, pro-proliferative effect on cancer cells in vitro. Several recent studies indicated that PRL action in vivo may be influenced by the hormonal milieu, e.g. other growth factors such as 17β-oestradiol (E2). Here, we explored the potential interplay between PRL and E2 in regulation of gene expression and cell growth. PRL alone induced either a weak or no proliferative response of T47D and BT-483 cells respectively, while it drastically enhanced cell proliferation in E2-stimulated cultures. Affymetrix microarray analysis revealed 12 genes to be regulated by E2, while 57 genes were regulated by PRL in T47D cells. Most of the PRL-regulated genes (42/57) were not previously described as PRL target genes, e.g. WT1 and IER3. One hundred and five genes were found to be regulated upon PRL/E2 co-treatment: highest up-regulation was found for EGR3, RUNX2, EGR1, MAFF, GLIPR1, IER3, SOCS3, WT1 and AREG. PRL and E2 synergised to regulate EGR3, while multiple genes were regulated additively. These data show a novel interplay between PRL and E2 to modulate gene regulation in breast cancer cells.

scholarly journals Chromatin forms nanoscale three-dimensional packing domains with fractal-like scaling behavior in vitro

2021 ◽  
Author(s):  
Yue Li ◽  
Vasundhara Agrawal ◽  
Ranya K. A. Virk ◽  
Eric Wayne Roth ◽  
Adam Eshein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Electron Microscopy ◽  
Chromatin Structure ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Three Dimensional ◽  
Chromatin Organization ◽  
Scaling Behavior ◽  
Wide Range

Chromatin organization over a wide range of length scales plays a critical role in the regulation of gene expression and deciphering these processes requires high-resolution, three-dimensional, quantitative imaging of chromatin structure in vitro. Herein we introduce ChromSTEM, a method that utilizes high angle annular dark-field imaging and tomography in scanning transmission electron microscopy combined with DNA-specific staining for electron microscopy. We utilized ChromSTEM to quantify chromatin structure in cultured cells and the scaling behavior of the chromatin polymer. We observed that chromatin forms spatially well-defined nanoscale domains which adopt a mass fractal internal structure up to around 100 nm in radius, with a radially decreasing mass-density from the center to the periphery. The morphological properties of the domains vary within the same cell line and seem to exhibit greater heterogeneity across cell lines, which might indicate how chromatin organization regulates gene expression.

scholarly journals Using Tumor-Infiltrating Immune Cells and a ceRNA Network Model to Construct a Prognostic Analysis Model of Thyroid Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Fan Zhang ◽  
Xiaohui Yu ◽  
Zheyu Lin ◽  
Xichang Wang ◽  
Tiantian Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Thyroid Carcinoma ◽  
Gene Expression Profiling ◽  
Immune Cells ◽  
Expression Profiling ◽  
Immune Cell ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Thyroid carcinoma is a solid malignant tumor that has had a fast-growing incidence in recent years. Our research used thyroid carcinoma gene expression profiling from TCGA (The Cancer Genome Atlas) database to identify differentially expressed ceRNAs. Using the gene expression profiling from 502 carcinoma thyroid tissues and 58 normal thyroid tissues from the TCGA database, we established the thyroid carcinoma-specific competitive endogenous RNA (ceRNA) network and found nine overall survival (OS)-associated genes (PRDM1, TGFBR3, E2F1, FGF1, ADAM12, ALPL, RET, AL928654.2, AC128688.2). We quantified the proportions of immune cells using the algorithm “CIBERSORT”, found three OS-associated immune cells (memory B cells, M0 macrophages, and activated dendritic cells), and established a thyroid carcinoma-specific immune cell network based on that. The good reliabilities AUC (area under the curve) of 10-year survival (0.955, 0.944, respectively) were accessed from the nomograms of genes and immune cells. Subsequently, by conducting co-expression analyses, we found a potential regulation network among ceRNAs and immune cells. Besides, we found that ALPL (alkaline phosphatase) and hsa-miR-204-5p were significantly correlated and that ALPL was related to activated dendritic cells. We took advantage of multi-dimensional databases to verify our discovery. Besides, immunohistochemistry (IHC) assays were conducted to detect the expression of a dendritic cell marker (CD11c) and ALPL in thyroid carcinoma (TC) and paracancerous tissues. In summary, our study found a potential mechanism in which hsa-miR-204-5p regulated ALPL in activated dendritic cells, which may allow them to play a critical role in thyroid carcinoma. These findings provide potential prognostic biomarkers and therapeutic targets for thyroid carcinoma.

scholarly journals Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model

2020 ◽  
Vol 34 ◽  
pp. 205873842097489
Author(s):  
Jiang Wang ◽  
Bo Wang ◽  
Xin Lv ◽  
Yingjie Wang
Keyword(s):  
Alveolar Bone ◽  
Immune Cell ◽  
Critical Role ◽  
Therapeutic Drug ◽  
Mice Model ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Tnf Α

Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.

scholarly journals A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linbang Wang ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Nian Zhou ◽  
Tianji Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Pearson Correlation ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Mcf7 Cells ◽  
Tumour Immunity ◽  
Immune Genes ◽  
Normal Tissues

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

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