Epigenetics最新文献

Eggs and sperm are responsible for the continuation of generations. Following the epigenetic reprogramming of the embryo, core epigenetic information present in the sperm and eggs is transmitted to offspring somatic cells prior to the blastula stage, which specifically influences gene expression in the cells. Differences in the patterns of DNA methylation between the paternal and maternal genomes are critical to regulating allele-specific gene expression in the developing embryo, constituting the basis of genomic imprinting in mammals. While the information on allele-specific epigenetic information has been limited to mammals, it is not clearly understood whether non-mammalian vertebrate gametes possess any sex-specific allelic epigenetic information and whether somatic cells maintain the allele-specific epigenetic information, particularly DNA methylation. To determine the landscape of DNA methylation in paternal and maternal alleles in a non-mammalian vertebrate, we profiled the methylome of egg in medaka fish and compared it with our previously published medaka sperm methylome. We identified a set of gamete-specific differentially methylated regions (DMRs) in the genome- medaka eggs maintained a significantly lower global methylation profile than the sperm. Based on our sequencing depth and data, 10 DMRs were hypermethylated, and 237 DMRs were hypomethylated in the eggs compared to the sperm methylome. Somatic cells in blastula maintained some of those parental gamete-specific DNA methylation profiles. Those DMRs are associated with 70 genes, suggesting that they may have imprinted-like functions and warrant further investigation.

Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring. Strikingly, these experiments also revealed that inducing miR-34c levels in PIEs enhances the expression of its own gene and that of miR-449 in these cells. The same induction of embryo miR-34/449 gene expression likely occurs after sperm-derived miR-34c is introduced into oocytes upon fertilization. Thus, suppression of this miRNA amplification system when sperm miR-34c levels are reduced in CSI stressed mice can explain how a comparable fold-suppression of miR-34/449 levels can be found in PIEs derived from them, despite sperm containing ~50-fold lower levels of these miRNAs than those already present in PIEs. We previously found that men exposed to early life trauma also display reduced sperm levels of miR-34/449. And here we show that miR-34c can also increase the expression of its own gene, and that of miR-449 in human embryonic stem cells, suggesting that human PIEs derived from men with low sperm miR-34/449 levels may also contain this potentially harmful defect.

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.

Studies suggest that clonal plants' ability to select habitats and forage in a heterogeneous environment is influenced by their past environment, with stress legacy potentially playing a crucial role. In this study, we examined parental ramets of Duchesnea indica Focke that were subject to either a control or lead-contaminated environment (past environment), and their newborn offspring were then transplanted into control, homogeneous lead or heterogeneous lead environment (present environment). We analysed how past and present environments affect plant growth and DNA methylation in offspring. The result shown that the DNA methylation loci composition of offspring was affected by the interaction of parental environment and offspring environment, and DNA methylation levels were higher in heterogeneous environments. Moreover, our findings indicate that offspring would thrive in the heterogeneous lead environment if they did not experience lead pollution in the past, their progeny will avoid lead toxicity by reducing underground biomass allocation. However, when the parents experienced lead stress environment, their biomass allocation strategies disappeared, and they prefer to grow in favourable patches to avoid lead-contaminated patches. We concluded that the integration of historical parental exposure to lead-contaminated and current information about their offspring's environment are impacting plant phenotypes. It is possible that the stress legacy from the parents has been transmitted to their offspring ramets, and the stress legacy is at least partly based on heritable epigenetic variation. The phenotypic variation regulated by the stress legacy affects the growth performance, biomass allocation strategy, and even the behaviour of D. indica.

Modelling the regulatory mechanisms that determine cell fate, response to external perturbation, and disease state depends on measuring many factors, a task made more difficult by the plasticity of the epigenome. Scanning the genome for the sequence patterns defined by Position Weight Matrices (PWM) can be used to estimate transcription factor (TF) binding locations. However, this approach does not incorporate information regarding the epigenetic context necessary for TF binding. CpG methylation is an epigenetic mark influenced by environmental factors that is commonly assayed in human cohort studies. We developed a framework to score inferred TF binding locations using methylation data. We intersected motif locations identified using PWMs with methylation information captured in both whole-genome bisulfite sequencing and Illumina EPIC array data for six cell lines, scored motif locations based on these data, and compared with experimental data characterizing TF binding (ChIP-seq). We found that for most TFs, binding prediction improves using methylation-based scoring compared to standard PWM-scores. We also illustrate that our approach can be generalized to infer TF binding when methylation information is only proximally available, i.e. measured for nearby CpGs that do not directly overlap with a motif location. Overall, our approach provides a framework for inferring context-specific TF binding using methylation data. Importantly, the availability of DNA methylation data in existing patient populations provides an opportunity to use our approach to understand the impact of methylation on gene regulatory processes in the context of human disease.

Early detection of hepatocellular carcinoma (HCC) can greatly improve the survival rate of patients. We aimed to develop a novel marker panel based on cell-free DNA (cfDNA) methylation for the detection of HCC. The differentially methylated CpG sites (DMCs) specific for HCC blood diagnosis were selected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then validated by the whole genome bisulphite sequencing (WGBS) of 12 paired HCC and paracancerous tissues. The clinical performance of the panel was evaluated using tissue samples [32 HCC, chronic liver disease (CLD), and healthy individuals] and plasma cohorts (173 HCC, 199 CLD, and 98 healthy individuals). The combination of G protein subunit beta 4 (GNB4) and Riplet had the optimal area under the curve (AUC) in seven candidates through TCGA, GEO, and WGBS analyses. In tissue validation, the GNB4 and Riplet showed an AUC of 100% with a sensitivity and specificity of 100% for detecting any-stage HCC. In plasma, it demonstrated a high sensitivity of 84.39% at 91.92% specificity, with an AUC of 92.51% for detecting any-stage HCC. The dual-marker panel had a higher sensitivity of 78.26% for stage I HCC than alpha-fetoprotein (AFP) of 47.83%, and a high sensitivity of 70.27% for detecting a single tumour (size ≤3 cm). In conclusion, we developed a novel dual-marker panel that demonstrates high accuracy in detecting HCC, surpassing the performance of AFP testing.

Atherosclerosis is a chronic inflammatory disease characterized by fatty plaque deposits on artery walls. Elevated plasma homocysteine (Hcy) levels are an independent risk factor for atherosclerosis. Research on the mechanism by which Hcy promotes atherosclerosis has gradually turned to epigenetic inheritance, but the correlation between Hcy and m6A (N6-methyladenosine) modification has not been reported. In this study, MeRIP-seq was performed on macrophages and Hcy-treated macrophages. GO and KEGG analyses were used to perform functional analysis of differentially methylated genes. qRT-PCR and western blot were taken to determine the expression of CD209, CD163L1, proinflammatory, and anti-inflammatory factors. Flow cytometry was used to detect the proportion of M2 macrophages. The results showed that after Hcy treatment, the overall m6A methylation of macrophages was down-regulated, and 856 differential methylation peaks were annotated to 781 genes. These included CD209 and CD163L1, whose m6A methylation was inhibited after treatment with Hcy. In addition, mRNA and protein expressions of CD209 and CD163L1 were also inhibited after Hcy treatment. Overexpression of CD209 or CD163L1 prevents the Hcy-induced decrease in the proportion of M2 macrophages. This article identified changes in the modification level of m6A in macrophages by Hcy and revealed the possible mechanism by which Hcy induces macrophage polarization.

Acute exposure to MK-801, the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, induces schizophrenia-like behavioural changes in juvenile male mice. However, the effects of acute MK-801 exposure on brain gene expression at the translation level remain unclear. Here, we conducted ribosome profiling analysis on the prefrontal cortex (PFC) of acute MK-801-exposed juvenile male mice. We found 357 differentially translated genes, with the N⁴-acetylcytidine (ac⁴C) consensus motif enriched in the transcripts with increased translation efficiency. Acetylated RNA immunoprecipitation sequencing revealed 148 differentially acetylated peaks, of which 121 were hyperacetylated, and 27 were hypoacetylated. Genes harbouring these peaks were enriched in pathways related to axon guidance, Hedgehog signalling pathway, neuron differentiation, and memory. Grin2a encodes an NMDA receptor subunit NMDAR2A, and its human orthologue is a strong susceptibility gene for schizophrenia. Grin2a mRNA was hyperacetylated and exhibited significantly increased translation efficiency. NMDAR2A protein level was increased in MK-801-exposed PFC. Pretreatment of Remodelin, an inhibitor of N-acetyltransferase 10, returned the NMDAR2A protein levels to normal and partially reversed schizophrenia-like behaviours of MK-801-exposed mice, shedding light on the possible role of mRNA acetylation in the aetiology of schizophrenia.