scholarly journals Transcriptome and Methylome Changes in Two Contrasting Mungbean Genotypes in Response to Drought Stress

2021 ◽  
Author(s):  
Peilei Zhao ◽  
Bao Ma ◽  
Chunmei Cai ◽  
Jihua Xu
Keyword(s):  
Dna Methylation ◽  
Genetic Variation ◽  
Drought Stress ◽  
Stress Responses ◽  
Methylation Status ◽  
Physiological Parameters ◽  
Gene Body ◽  
Sequence Context ◽  
Transcriptomic Data ◽  
Growth Distribution

Abstract Background: Due to drought stress, the growth, distribution, and production of mungbean is severely restricted. Previous study combining physiological and transcriptomic data indicated different genotypes of mungbean exhibited variable responses when exposed to drought stress. Aside from the genetic variation, the modifications of environmentally induced epigenetics alterations on mungbean drought-stress responses were still elusive. Results: In this study, firstly, we compared the drought tolerance capacity at seedling stages by detecting physiological parameters in two contrasting genotypes wild mungbean 61 and cultivar 70 in response to drought stress. We found that wild mungbean 61 showed lower level of MDA and higher levels of SOD, POD, and CAT, suggesting wild mungbean 61 exhibited stronger drought resistances. Transcriptomic analysis indicated totally 2659 differentially expressed genes (DEGs) were detected when 61 compared with 70 (C61 vs C70), and the number increased to 3121 in the comparison of drought-treated 70 compared with drought-treated 61 (D70 vs D61). In addition, when drought-treated 61 and 70 were compared with their controls, the DEGs were 1117 and 185 respectively, with more down-regulated DEGs than up-regulated in D61 vs C61, which was opposite in D70 vs C70. Interestingly, corresponding to this, after drought stress, more hypermethylated differentially methylated regions (DMRs) in 61 were detected and more hypomethylated DMRs in 70 were detected. Further analysis suggested that the main variations between 61 and 70 existed in CHH methylation in promoter. Moreover, the preference of methylation status alterations in D60 vs C60 and D70 vs C70 also fell in CHH sequence context. Further analysis of the correlation between DMRs and DEGs indicated in both D61 vs C61 and D70 vs C70, the DMRs in gene body was significantly negatively correlated with DEGs. Conclusion: The physiological parameters in this research suggested that wild mungbean 61 was more resistant to drought stress, with more hypermethylated DMRs and less hypomethylated DMRs after drought stress, corresponding to more down-regulated DEGs than up-regulated DEGs. Among the three DNA methylation contexts CG, CHG, and CHH, asymmetric CHH contexts were more dynamic and prone to be altered by drought stress and genotypic variations.

scholarly journals Whole-Genome DNA Methylation Analysis in Hydrogen Peroxide Overproducing Transgenic Tobacco Resistant to Biotic and Abiotic Stresses

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 178
Author(s):  
Ana L. Villagómez-Aranda ◽  
Luis F. García-Ortega ◽  
Irineo Torres-Pacheco ◽  
Ramón G. Guevara-González
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Methylation ◽  
Transgenic Tobacco ◽  
Stress Responses ◽  
Abiotic Stresses ◽  
Methylation Status ◽  
Physiological Adaptation ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Biotic And Abiotic Stresses

Epigenetic regulation is a key component of stress responses, acclimatization and adaptation processes in plants. DNA methylation is a stable mark plausible for the inheritance of epigenetic traits, such that it is a potential scheme for plant breeding. However, the effect of modulators of stress responses, as hydrogen peroxide (H2O2), in the methylome status has not been elucidated. A transgenic tobacco model to the CchGLP gene displayed high H2O2 endogen levels correlated with biotic and abiotic stresses resistance. The present study aimed to determine the DNA methylation status changes in the transgenic model to obtain more information about the molecular mechanism involved in resistance phenotypes. The Whole-genome bisulfite sequencing analysis revealed a minimal impact of overall levels and distribution of methylation. A total of 9432 differential methylated sites were identified in distinct genome regions, most of them in CHG context, with a trend to hypomethylation. Of these, 1117 sites corresponded to genes, from which 83 were also differentially expressed in the plants. Several genes were associated with respiration, energy, and calcium signaling. The data obtained highlighted the relevance of the H2O2 in the homeostasis of the system in stress conditions, affecting at methylation level and suggesting an association of the H2O2 in the physiological adaptation to stress functional linkages may be regulated in part by DNA methylation.

scholarly journals Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 539 ◽  
Author(s):  
Alexei J. Stuckel ◽  
Wei Zhang ◽  
Xu Zhang ◽  
Shuai Zeng ◽  
Urszula Dougherty ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Methylation Status ◽  
Cxcr4 Expression ◽  
Normal Colonic Mucosa ◽  
Gene Body ◽  
Expression Levels

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

scholarly journals DNA Methylation Changes and Its Associated Genes in Mulberry (Morus alba L.) Yu-711 Response to Drought Stress Using MethylRAD Sequencing

Plants ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 190
Author(s):  
Michael Ackah ◽  
Liangliang Guo ◽  
Shaocong Li ◽  
Xin Jin ◽  
Charles Asakiya ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Drought Stress ◽  
Methylation Status ◽  
Enrichment Analysis ◽  
Plant Genome ◽  
Pcr Analysis ◽  
Kegg Pathways ◽  
Wide Range ◽  
And Control

Drought stress remains one of the most detrimental environmental cues affecting plant growth and survival. In this work, the DNA methylome changes in mulberry leaves under drought stress (EG) and control (CK) and their impact on gene regulation were investigated by MethylRAD sequencing. The results show 138,464 (37.37%) and 56,241 (28.81%) methylation at the CG and CWG sites (W = A or T), respectively, in the mulberry genome between drought stress and control. The distribution of the methylome was prevalent in the intergenic, exonic, intronic and downstream regions of the mulberry plant genome. In addition, we discovered 170 DMGs (129 in CG sites and 41 in CWG sites) and 581 DMS (413 in CG sites and 168 in CWG sites). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicates that phenylpropanoid biosynthesis, spliceosome, amino acid biosynthesis, carbon metabolism, RNA transport, plant hormone, signal transduction pathways, and quorum sensing play a crucial role in mulberry response to drought stress. Furthermore, the qRT-PCR analysis indicates that the selected 23 genes enriched in the KEGG pathways are differentially expressed, and 86.96% of the genes share downregulated methylation and 13.04% share upregulation methylation status, indicating the complex link between DNA methylation and gene regulation. This study serves as fundamentals in discovering the epigenomic status and the pathways that will significantly enhance mulberry breeding for adaptation to a wide range of environments.

scholarly journals Effect of arsenic stress on 5-methylcytosine, photosynthetic parameters and nutrient content in arsenic hyperaccumulator Pteris cretica (L.) var. Albo-lineata

2020 ◽  
Author(s):  
Veronika Zemanová ◽  
Marek Popov ◽  
Daniela Pavlíková ◽  
Pavel Kotrba ◽  
František Hnilička ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Water Potential ◽  
Methylation Status ◽  
Nutrient Content ◽  
Physiological Parameters ◽  
Photosynthetic Parameters ◽  
High Exposure ◽  
Pteris Cretica ◽  
As Toxicity ◽  
Hyperaccumulator Plant

Abstract Background: Arsenic toxicity induces a range of metabolic responses in plants, including DNA methylation. The focus of this paper was on the relationship between As-induced stress and plant senescence in the hyperaccumulator Pteris cretica var. Albo-lineata (Pc-Al). We assume difference in physiological parameters and level of DNA methylation in young and old fronds as symptoms of As toxicity.Results: The As accumulation of Pc-Al fronds, grown in pots of haplic chernozem contaminated with 100 mg As kg-1 for 122 days, decreased with age. Content of As was higher in young than old fronds for variants with 100 mg As kg-1 (2800 and 2000 mg As kg-1 dry matter, respectively). The highest As content was determined in old fronds of Pc-Al grown in pots with 250 mg As kg-1. The increase with age was confirmed for determined nutrients – Cu, Mg, Mn, S and Zn. A significant elevation of all analysed nutrients was showed in old fronds. Arsenic accumulation affected DNA methylation status in fronds, but content of 5-methylcytosine (5mC) decreased only in old fronds of Pc-Al (from 25% to 12%). Determined photosynthetic processes showed a decrease of fluorescence, photosynthetic rate and chlorophylls of As treatments in young and old fronds. Water potential was decreased by As in both fronds. Thinning of the sclerenchymatous inner cortex and a reduction in average tracheid metaxylem in the vascular cylinder was showed in roots of As treatment. Irrespective to fronds age, physiological parameters positively correlated with a 5mC while negatively with direct As toxicity. Opposite results were found for contents of Cu, Mg, Mn, S and Zn.Conclusions: The results of this paper point to changes in the metabolism of the hyperaccumulator plant Pc-Al, upon low and high exposure to As contamination. The significant impact of As on DNA methylation was found in old fronds. Irrespective to fronds age, significant correlations were confirmed for 5mC and As toxicity. Our analysis of the very low water potential values and lignification of cell walls in roots showed that transports of assimilated metabolites and water between roots and fronds were reduced. As was showed by our results, epigenetic changes could affect studied parameters of the As hyperaccumulator plant Pc-Al, especially in old fronds.

scholarly journals Systematic Analysis of the DNA Methylase and Demethylase Gene Families in Rapeseed (Brassica napus L.) and Their Expression Variations After Salt and Heat stresses

2020 ◽  
Vol 21 (3) ◽  
pp. 953 ◽  
Author(s):  
Shihang Fan ◽  
Hongfang Liu ◽  
Jing Liu ◽  
Wei Hua ◽  
Shouming Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brassica Napus ◽  
Stress Responses ◽  
Methylation Status ◽  
Functional Characterization ◽  
Gene Families ◽  
Brassica Napus L ◽  
Systematic Analysis ◽  
Dna Methylase ◽  
Dna Demethylase

DNA methylation is a process through which methyl groups are added to the DNA molecule, thereby modifying the activity of a DNA segment without changing the sequence. Increasing evidence has shown that DNA methylation is involved in various aspects of plant growth and development via a number of key processes including genomic imprinting and repression of transposable elements. DNA methylase and demethylase are two crucial enzymes that play significant roles in dynamically maintaining genome DNA methylation status in plants. In this work, 22 DNA methylase genes and six DNA demethylase genes were identified in rapeseed (Brassica napus L.) genome. These DNA methylase and DNA demethylase genes can be classified into four (BnaCMTs, BnaMET1s, BnaDRMs and BnaDNMT2s) and three (BnaDMEs, BnaDML3s and BnaROS1s) subfamilies, respectively. Further analysis of gene structure and conserved domains showed that each sub-class is highly conserved between rapeseed and Arabidopsis. Expression analysis conducted by RNA-seq as well as qRT-PCR suggested that these DNA methylation/demethylation-related genes may be involved in the heat/salt stress responses in rapeseed. Taken together, our findings may provide valuable information for future functional characterization of these two types of epigenetic regulatory enzymes in polyploid species such as rapeseed, as well as for analyzing their evolutionary relationships within the plant kingdom.

scholarly journals Phylogenetic Shifts in Gene Body Methylation Correlate with Gene Expression and Reflect Trait Conservation

2019 ◽  
Vol 37 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Danelle K Seymour ◽  
Brandon S Gaut
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Evolution ◽  
Methylation Status ◽  
Evolutionary Constraint ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Plant Genomes ◽  
Genome Wide ◽  
Rates Of Molecular Evolution

Abstract A subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

Genetic and Epigenetic Regulation of the Gamma Globin Locus Is Associated with Fetal Hemoglobin Levels and Frequency of Pain in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3230-3230
Author(s):  
Blair Anderson ◽  
Ebenezer Enchia ◽  
Karen Soldano ◽  
Melanie Garrett ◽  
Jude Jonassaint ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variation ◽  
Sickle Cell Disease ◽  
Clinical Outcomes ◽  
Sickle Cell ◽  
Severe Pain ◽  
Methylation Status ◽  
Fetal Hemoglobin ◽  
European Ancestry ◽  
Cell Disease

Abstract Abstract 3230 Sickle cell disease (SCD) is caused by a single amino acid substitution of the β-globin chain of hemoglobin, resulting in abnormal red blood cells that occlude vessels, causing tissue damage, pain, and anemia. While all individuals with SCD have the same β-globin mutation, disease severity varies and is correlated with the concentration of retained fetal hemoglobin (HbF) (Akinsheye et al, 2011). After birth, a switch from γ- to β-globin gene expression occurs and HbF (α2γ2) is replaced by HbA (α2β2). In patients with SCD, increased levels of γ-globin can help compensate for the effects of the β-globin mutation. SCD patients with higher than normal retention of HbF frequently have more benign disease symptoms and longer life expectancy (Platt et al, 1994). Increased HbF expression through the use of hydroxyurea (HU) is a frequently used therapy and the only FDA-approved medication for SCD. However, due to the toxicity and inconsistent efficacy of HU, further understanding regarding the regulation of this “hemoglobin switch” is essential for developing alternative treatments. DNA methylation is central to the silencing of γ-genes during the switch to β-globin expression (Goren et al, 2006). Methylation marks are established by the DNA methyltransferase DNMT3A, which is recruited to the γ-promoter by the protein arginine methyltransferase, PRMT5 (Rank et al, 2010). We first hypothesized that genetic variation in DNMT3A and PRMT5 contributes to HbF levels. To test this, we performed a genetic association study on 603 unrelated, adult SCD patients. 21 haplotype-tagging SNPs in DNMT3A (n=17) and PRMT5 (n=4) were genotyped in the patients. SNPs were evaluated for association with HbF levels, as well as the occurrence of severe pain and narcotic use, which were used as surrogates for non-hemoglobin effects of HU. HbF levels were measured when the patients were at steady state and not taking HU. Severe pain was defined as a history of hospitalization for pain within a 12 month period. Narcotic use was defined as taking long- or short-acting narcotics to alleviate pain at home. To evaluate associations between the SNPs and clinical outcomes, we used linear and logistic regression (SAS Systems, Cary, NC), while controlling for age, sex, degree of European ancestry and HU treatment. European ancestry was estimated from 4331 genome-wide ancestry informative markers (Ashley-Koch et al, 2011). HbF levels were log-transformed prior to analysis in order to achieve a normal distribution. We corrected for multiple comparisons using the Li and Ji method (Li & Ji, 2005). Two SNPs in DNMT3A were significantly associated with the occurrence of severe pain and HbF levels after correcting for multiple testing. Additionally, two SNPs in DNMT3A and one in PRMT5 were nominally associated with severe pain, two SNPs in DNMT3A were nominally associated with narcotic use, and one SNP in PRMT5 was nominally associated with HbF levels. These findings demonstrate that genetic variation in key genes responsible for the regulation of DNA methylation at the γ-globin locus is associated with SCD clinical outcomes. We next hypothesized that the variability in clinical outcomes might be due to epigenetic variation at the γ-globin locus. In order to determine specific DNA methylation patterning of γ-globin genes (HBG1 and HBG2), we performed pyroseqencing subsequent to bisulfite treatment of DNA from a subset of 72 SCD patients, all of whom were HbSS, and 50% of whom were not on HU treatment. Percent methylation at the γ-globin locus was nominally associated with HbF levels among patients not taking HU (p=0.03), but not among patients taking HU. Additionally, we investigated whether SNPs predicted methylation status and identified two SNPs in DNMT3A (rs734693 and rs7583409) to be predictive of methylation status at the γ-globin locus. These data provide further insight into the complex regulation of the γ-globin locus and suggest that genetic variation in DNMT3A and PRMT5 is associated with clinical outcomes and methylation status in SCD patients. Future studies are needed to further investigate the impact of epigenetic processes as a potential mechanism for HbF expression and induction. Disclosures: Telen: GlycoMimetics: Research Funding.

scholarly journals Effect of arsenic stress on 5-methylcytosine, photosynthetic parameters and nutrient content in arsenic hyperaccumulator Pteris cretica (L.) var. Albo-lineata

2020 ◽  
Author(s):  
Veronika Zemanová ◽  
Marek Popov ◽  
Daniela Pavlíková ◽  
Pavel Kotrba ◽  
František Hnilička ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Water Potential ◽  
Methylation Status ◽  
Nutrient Content ◽  
Physiological Parameters ◽  
Photosynthetic Parameters ◽  
High Exposure ◽  
Arsenic Accumulation ◽  
Pteris Cretica ◽  
As Toxicity

Abstract Background Arsenic toxicity induces a range of metabolic responses in plants, including DNA methylation. The focus of this paper was on the relationship between As-induced stress and plant senescence in the hyperaccumulator Pteris cretica var. Albo-lineata (Pc-Al). We assume difference in physiological parameters and level of DNA methylation in young and old fronds as symptoms of As toxicity. Results The As accumulation of Pc-Al fronds, grown in pots of haplic chernozem contaminated with 100 mg As kg-1 for 122 days, decreased with age. Content of As was higher in young than old fronds. The highest As content was determined in old fronds of Pc-Al grown in pots with 250 mg As kg-1. The increase with age was confirmed for determined nutrients – Cu, Mg, Mn, S and Zn. A significant elevation of analysed nutrients was showed in old fronds. Arsenic accumulation affected DNA methylation status in fronds, but content of 5-methylcytosine (5mC) decreased only in old fronds of Pc-Al (from 25% to 12%). Determined photosynthetic processes showed a decrease of fluorescence, photosynthetic rate and chlorophylls of As treatments in young and old fronds. Water potential was decreased by As in both fronds. Thinning of the sclerenchymatous inner cortex and a reduction in average tracheid metaxylem in the vascular cylinder was showed in roots of As treatment. Irrespective to fronds age, physiological parameters positively correlated with a 5mC while negatively with direct As toxicity. Opposite results were found for contents of Cu, Mg, Mn, S and Zn. Conclusions The results of this paper point to changes in the metabolism of the hyperaccumulator plant Pc-Al, upon low and high exposure to As contamination. The significant impact of As on DNA methylation was found in old fronds. Irrespective to fronds age, significant correlations were confirmed for 5mC and As toxicity. Our analysis of the very low water potential values and lignification of cell walls in roots showed that transports of assimilated metabolites and water between roots and fronds were reduced. As was showed by our results, epigenetic changes could affect studied parameters of the As hyperaccumulator Pc-Al, especially in old fronds.

scholarly journals Phylogenetic shifts in gene body methylation correlate with gene expression and reflect trait conservation

2019 ◽  
Author(s):  
Danelle K. Seymour ◽  
Brandon S. Gaut
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Evolution ◽  
Methylation Status ◽  
Evolutionary Constraint ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Plant Genomes ◽  
Genome Wide ◽  
Rates Of Molecular Evolution

ABSTRACTA subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.

scholarly journals The relationship among Girdin DNA methylation, its high expression, and immune infiltration in hepatocellular carcinoma: Clues from in silico analysis

2021 ◽  
Vol 41 (3) ◽  
Author(s):  
Cheng Zhang ◽  
Yang Ke ◽  
Xuefen Lei ◽  
Xin Liu ◽  
Hai Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Methylation ◽  
Mrna Expression ◽  
Methylation Status ◽  
Cancer Genome ◽  
High Expression ◽  
Gene Body ◽  
Immune Infiltration ◽  
Normal Tissues ◽  
The Relationship

Abstract Objective: The aim of the present study was to explore the relationship among Girdin DNA methylation, its high expression, and immune infiltration in human hepatocellular carcinoma (HCC). Materials and methods: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC) databases were used to compare Girdin mRNA expression between HCC tissues and normal tissues, and determine the relationship between Girdin expression and HCC prognosis. TCGA database was also used to analyze the expression of Girdin and its methylation status, as well as the relationship between Girdin DNA methylation and HCC prognosis. The Tumor IMmune Estimation Resource (TIMER) database was used to explore the correlation between Girdin expression and HCC immune infiltration. Results: Girdin expression was elevated in HCC tissues compared with that in normal tissues. The degree of methylation at cg03188526, a CpG site in the Girdin gene body, was positively correlated with Girdin mRNA expression, while high Girdin expression and cg03188526 hypermethylation were both correlated with poor HCC prognosis. Additionally, HCC tissue with high Girdin expression exhibited abundant immune infiltration, and the high Girdin expression was associated with a worse prognosis in macrophage-enriched HCC specimens. Conclusion: Our findings indicated that Girdin likely functions as an oncogene in HCC and that hypermethylation at cg03188526 in the Girdin gene body may explain the high Girdin expression levels in HCC tissue. Furthermore, we report for the first time that the adverse effects of high Girdin expression in HCC patients may be partially mediated by tumor macrophage infiltration.

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