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PubMed2001

5-Methylcytosine DNA glycosylase participates in the genome-wide loss of DNA methylation occurring during mouse myoblast differentiation.

Changes in gene expression during mouse myoblast differentiation were monitored by DNA microarray hybridisation. Four days after the onset of differentiation 2.37% of the genes increased in activity from a value of zero, whereas during the same time 1.68% of total genes had decreased expression. During the first 24 h of differentiation an average of 700 000 CpG sites per haploid genome were demethylated. Maximal loss of DNA methylation is attained after 2 days of differentiation, followed by a gradual remethylation. The highest demethylation is observed in highly repeated DNA sequences, followed by single copy sequences. When DNA replication is inhibited by aphidicolin or L-mimosine this genome-wide demethylation is still observed. During the first 3 h of differentiation there is an increase in the number of hemimethylated CpG sites, which disappear rapidly during the course of genome-wide hypomethylation. Transfection of cells with an antisense morpholino oligonucleotide to 5-methylcytosine DNA glycosylase (G/T mismatch DNA glycosylase) decreases both the activity of the enzyme and genome-wide demethylation. It is concluded that the genome-wide loss of DNA methylation in differentiating mouse myoblasts occurs in part by formation of hemimethylated CpG sites, which can serve as the substrate for 5-methylcytosine-DNA glycosylase.

Animals↗

PubMed2003

Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation.

Previously we showed reduced protein and mRNA expression of the SHP1 gene in lymphoma/leukemia cell lines and patient specimens by Northern blot, RT-PCR, Western blot, and immunohistochemical analyses. In this study, aberrant methylation in the SHP1 gene promoter was detected in many B-cell leukemia/lymphoma cell lines as well as in patient specimens, including diffuse large B-cell lymphoma (methylation frequency 93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%) by methylation-specific PCR, bisulfite sequencing, and restriction enzyme-mediated PCR analyses. The methylation frequency was significantly higher in high-grade MALT lymphoma cases (100%) than in low-grade MALT lymphoma cases (70%), which correlated well with the frequency of no expression of SHP1 protein in high-grade (80%) and low-grade MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression. SHP1 protein expression was recovered in B-cell lines after the treatment of the demethylating reagent: 5-aza-2'-deoxycytidine. Transfection of the intact SHP1 gene to the hematopoietic cultured cells, which show no expression of the SHP1 gene, induced growth inhibition, indicating that gene silencing of the SHP1 gene by aberrant methylation plays an important role to get the growth advantage of the malignant lymphoma/leukemia cells. The extraordinarily high frequency (75 to 100%) of CpG methylation of the SHP1 gene in B-cell lymphoma/leukemia patient specimens indicates that the SHP1 gene silencing is one of the critical events to the onset of malignant lymphomas/leukemias as well as important implications for the diagnostic or prognostic markers and the target of gene therapy. These data support the possibility that the SHP1 gene is one of the tumor suppressor genes.

Base Sequence↗

PubMed2006

De novo induction of a cancer/testis antigen by 5-aza-2'-deoxycytidine augments adoptive immunotherapy in a murine tumor model.

Recent studies suggest that immunotherapy targeting specific tumor-associated antigens (TAAs) may be beneficial in cancer patients. However, most of these TAAs are tumor type specific and heterogeneous among patients, thus limiting their applications. Here, we describe the de novo induction of a cancer/testis antigen (CTA) for immunotherapy of tumors of various histologies. The murine CTA P1A, normally expressed only in a few tumor lines, could be induced de novo in all P1A-negative cancer lines of eight histologic origins in vitro and in various murine xenografts by systemic administration of 5-aza-2'-deoxycytidine. The induction of P1A expression correlated strongly with demethylation of the CpG island in the promoter region of this gene. The induced antigen was processed and presented properly for recognition by H-2L(d)-restricted P1A-specific CTLs. The combination of a demethylating agent and adoptive transfer of P1A-specific CTL effectively treated lung metastases in syngeneic mice challenged with P1A-negative 4T1 mammary carcinoma cells. These data show a novel strategy of combined chemoimmunotherapy of cancer targeting a CTA induced de novo in a broad range of tumor histologies, and support further evaluation of chromatin-remodeling agents for human cancer therapy.

Animals↗

PubMed2004

Expression of cancer-testis antigen (CTA) genes in intrahepatic cholangiocarcinoma.

BACKGROUND: Cancer-testis antigens (CTA), such as MAGE, are selectively expressed in various types of human neoplasms but not in normal tissues other than testis. This characteristic feature of CTA makes them promising antigens for cancer-specific immunotherapy. METHODS: We investigated the expression of five genes, including MAGE-1, MAGE-3, NY-ESO-1, SCP-1, and SSX-4, in 20 surgical samples of intrahepatic cholangiocarcinomas (IHCC) using reverse transcription-polymerase chain reaction. To visualize the localization of MAGE proteins, we performed immunohistochemical studies. Furthermore, the correlation between the CTA expression and DNA methylation status was studied in three bile duct cancer cell lines. RESULTS: Expression of MAGE-1, MAGE-3, NY-ESO-1, SCP-1, and SSX-4 was recognized in 4, 4, 2, 6, and 3 of all 20 cases, respectively. In contrast, the expressions of five genes were not recognized at all in the corresponding normal tissues. In 10 cases (50%), the tumors expressed at least one of the five CTA. An immunohistochemical analysis of MAGE proteins demonstrated homogenous or focal distributions in cytoplasm of the IHCC. Using a demethylating agent, MAGE-1, NY-ESO-1, SCP-1, and SSX-4 were induced in two of three cell lines, whereas MAGE-3 was not. CONCLUSIONS: Half of the tumor tissues of IHCC expressed at least one of the CTA. Some of the patients with IHCC, therefore, should be candidates for potentially useful cancer-specific immunotherapy.

Aged↗

PubMed2005

Abnormal expression of JUNB gene in hepatocellular carcinoma.

JUNB is an activating protein-1 transcription factor and is important in the control of cell growth, differentiation and neoplastic transformation. To understand the role of JUNB in human hepatocellular carcinoma (HCC), we examined 30 HCCs and their paired non-cancerous tissues by real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis for the expression of JUNB. The results showed that JUNB was underexpressed in most of the cancerous tissues (73.3%). Mutational analysis of the entire gene, and methylation analysis of CpG sites at the promoter area of JUNB, showed no specific changes between cancerous and paired non-cancerous tissues. Our results suggest that the down-regulated JUNB expression in HCC was due to an unknown mechanism, and not to methylation of the CpG site at the promoter or mutation in the coding areas. We further analyzed the relationship between JUNB, P16 and cyclin D1 expression. Our results showed that JUNB and P16 produced similar expression patterns, however, inverse expression patterns were found between JUNB and cyclin D1 in most of the HCC tissues. We also found a discrepancy between the expression of JUNB and cyclin D1 in some of the HCC tissue. From these results, we suggest that two pathways (JUNB-related and JUNB-unrelated) may be involved in the development of HCC.

Adult↗

PubMed2024

A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis.

OBJECTIVE: Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study. METHODS: We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. RESULTS: This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development. CONCLUSION: Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Humans↗

PubMed2003

DNA methylation in haematological malignancies: the role of decitabine.

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.

Animals↗

PubMed1997

Undermethylation of Alu sequences in ICF syndrome: molecular and in situ analysis.

The methylation status of young Alu sequences was investigated in four ICF patients. In fibroblast and leukocyte DNAs, Alu repeats were either undermethylated (HhaI and HpaII digestion) or demethylated (BstUI digestion), in contrast with the methylated status of Alus in control subjects. The methylation profile exhibited in ICF patients reproduces the normal profile of placental or sperm DNA. High-sensitivity immunocytochemical detection of HhaI and HpaII restriction sites on metaphase chromosomes provided further evidence of this undermethylation. The DNA methylation defect in ICF patients, first detected in satellite DNAs (constitutive heterochromatin) and CpG islands of genes on the inactive X chromosome (facultative heterochromatin), thus includes Alu sequences that are widely distributed throughout the human genome.

Base Sequence↗

PubMed2026

Methylome profiling of SetDB1-deficient ESCs reveals coordinated epigenetic cross-talk during pluripotency.

SetDB1 is best known for catalyzing H3K9me3, but it also influences H3K27me3 deposition, CTCF-binding, and DNA methylation (DNAme). Given the interplay between DNAme and the other epigenetic features, we profiled DNAme following Setdb1 knockout (KO) in ground-state and serum-grown mouse embryonic stem cells (ESCs) to illuminate DNAme-dependent and -independent functions of SetDB1. Time-course whole-genome bisulfite sequencing of serum-grown ESCs shows that nearly half of SetDB1 binding sites are enriched with DNAme and H3K9me3, primarily at retrotransposons. Upon Setdb1 KO, both H3K9me3 and DNAme are reduced, with DNAme rapidly removed at many sites by TET enzymes. Some retrotransposons, primarily IAPs, are TET-resistant and lose DNAme slowly via passive dilution. Notably, SetDB1-mediated regulation of H3K27me3, CTCF-binding, and SMAD3 are uncoupled from the DNAme-H3K9me3 axis, and from each other. AlphaFold modeling and co-immunoprecipitation mass spectrometry suggest this uncoupling involves competitive binding to distinct SetDB1 protein domains, highlighting the complex coordination underlying SetDB1 functions.

AlphaFold modeling↗

PubMed2004

Correlation between methylation profile of promoter cpg islands of seven metastasis-associated genes and their expression states in six cell lines of liver origin.

BACKGROUND & OBJECTIVE: DNA methylation has been regarded as an important epigenetic signature reflecting the transcription state of DNA in cells. This study was to assess the correlation between methylation state of promoter CpG islands of metastasis-associated genes and their expression in 6 liver cell lines, including 5 cancerous. METHODS: Methylation specific polymerase chain reaction method (MSP) and DNA sequencing verification were used to analyze the methylation state of promoter CpG islands of 7 genes (ASPH, ENO3, ITGA9, LRP6, MTHFD2, OXCT, and SRP72) in 5 liver cancer cell lines (BEL-7402, SMMC-7721, Hep3B, HepG2, and HCCLM3), and 1 immortalized liver cell line (L-02). Expression of 6 genes in this list was assessed by the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. RESULTS: The methylation state of genes was either unmethylated or heterozygously methylated in these 7 liver cell lines. Except for no expression of OXCT gene was detected by RT-PCR in both HepG2 and HCCLM3 cells where it was heterozygously methylated, there was expression of genes in all the remaining cases. CONCLUSION: Although expression state of genes in this study supported the general notion that hypermethylation state of promoter CpG islands of genes represents the silenced state of gene transcription, there were exceptions. Therefore, other mechanisms are likely to contribute to the observed expression state of these 7 genes in this study.

Calcium-Binding Proteins↗

PubMed2006

Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing.

Expression levels of microRNAs (miRNAs) are globally reduced in cancer compared with matched normal tissues, and miRNA function has recently been implicated in tumorigenesis. To test whether epigenetic silencing contributes to miRNA suppression in tumors, lung cancer cells were treated with inhibitors of DNA methylation or histone deacetylation. No significant alteration in miRNA expression was detected using microarray profiling. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). No mutations were detected within any of the short mature miRNA sequences. In addition to previously reported polymorphisms, 1 sequence variant in a precursor miRNA and 15 variants in primary miRNA (pri-miRNA) transcripts were identified. Despite pri-miRNAs having dramatic changes in the predicted secondary folding structure flanking putative cleavage sites, processing and miRNA maturation were not affected in vivo. Thus, genetic variants in miRNA precursors are common in cancer cells but are unlikely to have physiologic significance.

Acetylation↗

PubMed2006

High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer.

Cell surface mannose 6-phosphate/insulin-like growth factor II receptors (M6P/IGF2R) bind and target exogenous insulin-like growth factor II (IGF2) to the prelysosomes where it is degraded. Loss of heterozygosity (LOH) for M6P/IGF2R is found in cancers, with mutational inactivation of the remaining allele. We exploited the normal allele-specific differential methylation of the M6P/IGF2R intron 2 CpG island to rapidly evaluate potential LOH in ovarian cancers, since every normal individual is informative. To this end, we developed a method for bisulfite modification of genomic DNA in 96-well format that allows for rapid methylation profiling. We identified ovarian cancers with M6P/IGF2R LOH, but unexpectedly also found frequent abnormal acquisition of methylation on the paternally inherited allele at intron 2. These results demonstrate the utility of our high-throughput method of bisulfite modification for analysis of large sample numbers. They further show that the methylation status of the intron 2 CpG island may be a useful indicator of LOH and biomarker of disease.

Alleles↗

PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗

PubMed2006

A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats.

Aberrations in methylation profile of the genome occur in human cancers induced by folate deficiency. To elucidate the underlying mechanism, male F344 rats were fed a diet deficient in l-methionine and devoid of folic acid and choline (FMD diet), which is known to induce hepatocellular carcinomas. We investigated changes in the DNA methylation machinery, namely, de novo DNA methyltransferases (Dnmt3a and 3b), maintenance DNA methyltransferase (Dnmt1), and methyl CpG binding proteins (MBDs), in rat livers during early stages of tumorigenesis. RT-PCR and Western blot analyses revealed differential expression of these proteins in the livers of rats fed the FMD diet. Although the hepatic Dnmt1 mRNA level declined with age (P < 0.001), it was elevated (P < 0.001) in deficient rats compared with controls. The changes in hepatic Dnmt1 protein level with the diet correlated with its mRNA levels (r = 0.60, P = 0.002). Similarly, the Dnmt3a mRNA level was elevated in rats fed the FMD diet (P < 0.001), whereas the Dnmt3b level (mRNA and protein) was not affected by diet or age. Compared with controls, hepatic MBD1-3 RNA levels increased (P < 0.001) and the protein levels of MBD1, 2, and 4 were elevated (P < 0.001) in the deficient rats. In both diet groups, hepatic MBD2 protein decreased (P < 0.001), whereas MeCP2 protein increased (P < 0.001) with age. These results demonstrate that a combined folate and methyl deficiency alters components of the DNA methylation machinery by both transcriptional and posttranscriptional mechanisms during early stages of hepatocarcinogenesis.

Animals↗

PubMed2001

DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.

ICF (immunodeficiency, centromeric region instability and facial anomalies) is a recessive disease caused by mutations in the DNA methyltransferase 3B gene (DNMT3B). Patients have immunodeficiency, chromosome 1 (Chr1) and Chr16 pericentromeric anomalies in mitogen-stimulated lymphocytes, a small decrease in overall genomic 5-methylcytosine levels and much hypomethylation of Chr1 and Chr16 juxtacentromeric heterochromatin. Microarray expression analysis was done on B-cell lymphoblastoid cell lines (LCLs) from ICF patients with diverse DNMT3B mutations and on control LCLs using oligonucleotide arrays for approximately 5600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes had consistent and significant ICF-specific changes in RNA levels. Half of these genes play a role in immune function. ICF-specific increases in immunoglobulin (Ig) heavy constant mu and delta RNA and cell surface IgM and IgD and decreases in Ig(gamma) and Ig(alpha) RNA and surface IgG and IgA indicate inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1, a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the pro-apoptotic protein kinase C eta gene. ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration or survival of lymphoid cells, namely, transcription factor negative regulator ID3, the enhancer-binding MEF2C, the iron regulatory transferrin receptor, integrin beta7, the stress protein heme oxygenase and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17. No differences in promoter methylation were seen between ICF and normal LCLs for three ICF upregulated genes and one downregulated gene by a quantitative methylation assay [combined bisulfite restriction analysis (COBRA)]. Our data suggest that DNMT3B mutations in the ICF syndrome cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation and migration.

Cell Line↗

PubMed2002

Restriction landmark genomic scanning for DNA methylation in cancer: past, present, and future applications.

The field of molecular biology was revolutionized by the advent of gel electrophoresis. Restriction landmark genomic scanning (RLGS) is a type of two-dimensional electrophoresis employed in the genome-wide assessment of genomic alterations. RLGS has been used to study genetic and epigenetic changes in normal tissues, primary tumors, cancer cell lines, and various organisms such as mice, rats, hamsters, bacteria, and plants. An RLGS profile displays over 2000 radiolabeled restriction landmark sites in a single assay. When conducted with methylation-sensitive restriction enzymes whose sites are preferentially located in CpG island regulatory regions, RLGS becomes a very versatile tool for the investigation of both normal and aberrant methylation patterns. Early studies performed on tumor DNA were mainly descriptive in nature, essentially a catalogue of loci that were changed to varying degrees in different tumor types. Over time, as investigators have become more proficient with RLGS and have undertaken high-throughput studies, the need for efficient cloning, imaging, and analysis systems has become paramount. Current studies focus on identifying specific genes and pathways involved in deregulated methylation in cancer. As such, RLGS analysis of tumor samples has made tremendous contributions to our understanding of the role of DNA methylation in cancer. Future directions will take advantage of the abundant genomic sequence data available to link all of the RLGS loci to genes and create biologically relevant methylation profiles of cancer. This review discusses practical considerations of using RLGS as a genome scanning tool and the past, present, and future applications in cancer biology.

Animals↗

PubMed2004

Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression.

During herpes simplex virus type 1 (HSV-1) latency, gene expression is tightly repressed except for the latency-associated transcript (LAT). The mechanistic basis for this repression is unknown, but its global nature suggests regulation by an epigenetic mechanism such as DNA methylation. Previous work demonstrated that latent HSV-1 genomes are not extensively methylated, but these studies lacked the resolution to examine methylation of individual CpGs that could repress transcription from individual promoters during latency. To address this point, we employed established models to predict genomic regions with the highest probability of being methylated and, using bisulfite sequencing, analyzed the methylation profiles of these regions. We found no significant methylation of latent DNA isolated from mouse dorsal root ganglia in any of the regions examined, including the ICP4 and LAT promoters. This analysis indicates that methylation is unlikely to play a major role in regulating HSV-1 latent gene expression. Subsequently we focused on differential histone modification as another epigenetic mechanism that could regulate latent transcription. Chromatin immunoprecipitation analysis of the latent HSV-1 DNA repeat regions demonstrated that a portion of the LAT region is associated with histone H3 acetylated at lysines 9 and 14, consistent with a euchromatic and nonrepressed structure. In contrast, the chromatin associated with the HSV-1 DNA polymerase gene located in the unique long segment was not enriched in H3 acetylated at lysines 9 and 14, suggesting a transcriptionally inactive structure. These data suggest that histone composition may be a major regulatory determinant of HSV latency.

Acetylation↗

PubMed2000

Methylation and expression of amplified esterase genes in the aphid Myzus persicae (Sulzer).

Most populations of the aphid Myzus persicae have amplified genes (up to 80 copies) encoding the insecticide-detoxifying esterase E4. This paper reports the analysis of methylation of the E4 gene and its flanking DNA with the use of methylation-sensitive restriction enzymes, CpG profiling and bisulphite sequencing. In combination these show that E4 has 5-methylcytosine confined to CpG doublets, as previously shown for vertebrate genomes; this is the first such report for an insect gene. The methylation is present within the gene but absent from upstream regions, including the 5' CpG-rich region around the start of transcription, and from 3' flanking DNA. Methylated E4 genes are expressed; loss of the 5-methylcytosine is correlated with a loss of transcription, although this is not accompanied by a global loss of the 5-methylcytosine present in the aphid genome. These results suggest that the methylation of E4 has a positive role in expression, and call into question the widely held view that methylation in invertebrate genomes is confined to regions that do not contain genes and that methylation is always associated with gene silencing.

Animals↗