Epigenetic Modification Patterns Research Articles

Complete genome sequence and epigenetic profile of Bacillus velezensis UCMB5140 used for plant and crop protection in comparison with other plant-associated Bacillus strains.

The application of biocontrol biopesticides based on plant growth-promoting rhizobacteria (PGPR), particularly members of the genus Bacillus, is considered a promising perspective to make agricultural practices sustainable and ecologically safe. Recent advances in genome sequencing by third-generation sequencing technologies, e.g., Pacific Biosciences' Single Molecule Real-Time (PacBio SMRT) platform, have allowed researchers to gain deeper insights into the molecular and genetic mechanisms of PGPR activities, and to compare whole genome sequences and global patterns of epigenetic modifications. In the current work, this approach was used to sequence and compare four Bacillus strains that exhibited various PGPR activities including the strain UCMB5140, which is used in the commercial biopesticide Phytosubtil. Whole genome comparison and phylogenomic inference assigned the strain UCMB5140 to the species Bacillus velezensis. Strong biocontrol activities of this strain were confirmed in several bioassays. Several factors that affect the evolution of active PGPR B. velezensis strains were identified: (1) horizontal acquisition of novel non-ribosomal peptide synthetases (NRPS) and adhesion genes; (2) rearrangements of functional modules of NRPS genes leading to strain specific combinations of their encoded products; (3) gain and loss of methyltransferases that can cause global alterations in DNA methylation patterns, which eventually may affect gene expression and regulate transcription. Notably, we identified a horizontally transferred NRPS operon encoding an uncharacterized polypeptide antibiotic in B. velezensis UCMB5140. Other horizontally acquired genes comprised a possible adhesin and a methyltransferase, which may explain the strain-specific methylation pattern of the chromosomal DNA of UCMB5140. KEY POINTS: • Whole genome sequence of the active PGPR Bacillus velezensis UCMB5140. • Identification of genetic determinants responsible for PGPR activities. • Role of methyltransferases and epigenetic mechanisms in evolution of bacteria.

Key Relevance of Epigenetic Programming of Adiponectin Gene in Pathogenesis of Metabolic Disorders.

Significant health and social burdens have been created by the growth of metabolic disorders like type 2 diabetes mellitus (T2DM), atherosclerosis, and non-alcoholic steatohepatitis, worldwide. The number of the affected population is as yet rising, and it is assessed that until 2030, 4-5 million individuals will acquire diabetes. A blend of environmental, genetic, epigenetic, and other factors, such as diet, are accountable for the initiation and progression of metabolic disorders. Several researches have shown strong relevance of adiponectin gene and metabolic disorders. In this review, the potential influence of epigenetic mechanisms of adiponectin gene "ADIPOQ" on increasing the risk of developing metabolic disorders and their potential in treating this major disorder are discussed. Various studies have postulated that a series of factors such as maternal High fat diet (HFD), oxidative stress, pro-inflammatory mediators, sleep fragmentation throughout lifetime, from gestation to old age, could accumulate epigenetic marks, including histone remodeling, DNA methylation, and microRNAs (miRNAs) that, in turn, alter the expression of ADIPOQ gene and result in hypoadiponectinemia which precipitates insulin resistance (IR) that in turn might induce or accelerate the onset and development of metabolic disorder. A better understanding of global patterns of epigenetic modifications and further their alterations in metabolic disorders will bestow better treatment strategies design.

TriPCE: A Novel Tri-Clustering Algorithm for Identifying Pan-Cancer Epigenetic Patterns.

Epigenetic alteration is a fundamental characteristic of nearly all human cancers. Tumor cells not only harbor genetic alterations, but also are regulated by diverse epigenetic modifications. Identification of epigenetic similarities across different cancer types is beneficial for the discovery of treatments that can be extended to different cancers. Nowadays, abundant epigenetic modification profiles have provided a great opportunity to achieve this goal. Here, we proposed a new approach TriPCE, introducing tri-clustering strategy to integrative pan-cancer epigenomic analysis. The method is able to identify coherent patterns of various epigenetic modifications across different cancer types. To validate its capability, we applied the proposed TriPCE to analyze six important epigenetic marks among seven cancer types, and identified significant cross-cancer epigenetic similarities. These results suggest that specific epigenetic patterns indeed exist among these investigated cancers. Furthermore, the gene functional analysis performed on the associated gene sets demonstrates strong relevance with cancer development and reveals consistent risk tendency among these investigated cancer types.

Comprehensive analysis of long noncoding RNA (lncRNA)-chromatin interactions reveals lncRNA functions dependent on binding diverse regulatory elements

Over the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, many of which play crucial roles in normal physiology and human disease. LncRNAs can interact with chromatin and then recruit protein complexes to remodel chromatin states, thus regulating gene expression. However, how lncRNA-chromatin interactions contribute to their biological functions is largely unknown. Here, we collected and constructed an atlas of 188,647 lncRNA-chromatin interactions in human and mouse. All lncRNAs showed diverse epigenetic modification patterns at their binding sites, especially the marks of enhancer activity. Functional analysis of lncRNA target genes further revealed that lncRNAs could exert their functions by binding to both promoter and distal regulatory elements, especially the distal regulatory elements. Intriguingly, many important pathways were observed to be widely regulated by lncRNAs through distal binding. For example, NEAT1, a cancer lncRNA, controls 13.3% of genes in the PI3K-AKT signaling pathway by interacting with distal regulatory elements. In addition, "two-gene" signatures composed of a lncRNA and its distal target genes, such as HOTAIR-CRIM1, provided significant clinical benefits relative to the lncRNA alone. In summary, our findings underscored that lncRNA-distal interactions were essential for lncRNA functions, which would provide new clues to understand the molecular mechanisms of lncRNAs in complex disease.

Genetic Contexts Characterize Dynamic Histone Modification Patterns Among Cell Types.

Histone modifications play critical roles in mammalian development, regulating chromatin structure and gene expression. Dynamic histone modifications among cell types have been shown to associate with changes in mammalian development. However, how to quantitatively measure the histone modification alterations and how histone modifications vary across cell types under different genetic contexts remain largely unexplored and whether these changes are related to the primary DNA sequence remains limited. Here, we employed an entropy-based method to measure histone modification alterations in six definite genomic regions across five cell types and identified lineage-specific histone modification genes. We observed that histone modification alterations prefer to enrich in 5'-UTR exons, and also in 3'-UTR exons and its downstream. Then we built a model to predict the histone modification patterns from the primary DNA sequence. We found that the frequencies of k-mer sequence compositions are predictive of histone modification patterns, suggesting that the primary DNA sequence correlated with the histone modification alterations among cell types. Additionally, the lineage-specific histone modification genes display a higher conservation and lower GC-content. Together, we performed a systematic analysis for histone modification alterations and demonstrated how to identify genomic region-specific elements of epigenetic and genetic regulation and histone modification patterns across different cell types.

Advances in the Profiling of Single‐Cell DNA Modifications

AbstractEpigenetic modifications on DNA include canonical 5‐methylcytosine (5mC) and its iteratively oxidized derivatives mediated by TET dioxygenase: 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxycytosine (5caC). All of them have been recognized to play important roles in gene expression regulation and to be indispensable for normal mammalian reproduction and development. In order to understand the mechanisms underlying these roles, over the past few decades, technical advances have been made to comprehensively profile the distribution pattern of bulk epigenetic modifications in genomic DNA. Recently, single‐cell methods have identified the epigenetic patterns even within an individual cell. This review focuses on single‐cell DNA epigenetic modifications sequencing technologies and their applications, and gives prospects on the development of single‐cell methods based on bisulfite‐free strategy.

Hypomethylation at non-CpG/CpG sites in the promoter of HIF-1\u03b1 gene combined with enhanced H3K9Ac modification contribute to maintain higher HIF-1\u03b1 expression in breast cancer

HIF-1α has a broad impact on tumors, including enhanced utilization of glucose, tumor cell stemness, migration, metastasis and so on. In pilot study, we found that the expression of HIF-1α significantly increased in breast cancer cell lines and tissue samples with higher malignant behaviors and decreased in luminal subtype breast cancer cells and tissue samples. We analyzed and found there is one large CpG island in HIF-1α promoter around transcription start site, and the hypermethylation occurred at these CpGs and their surrounding non-CpGs sites. Epigenetic events driving tumorigenesis has been characterized. However, knowledge is lacking on the non-CpGs methylation of HIF-1α promoter in breast cancer cells. We validated that non-CpGs methylation can directly regulate HIF-1α expression by luciferase activity assay. We also found DNMT3a and Mecp2 play vital role in methylation at non-CpGs and CpGs sites. In addition, we noticed that H3K9ac modification could promote the transcription of HIF-1α in MDA-MB-231 cells by binding to the region contained hypomethylated non-CpG and CpG sites. Taken together, the hypomethylation status at non-CpG and CpG loci in HIF-1α promoter and H3K9ac modification together contribute to maintain higher HIF-1αactivity in invasive breast cancer cells when compared with the non-invasive breast cancer cells, which may establish a tissue-specific epigenetic modification pattern and point to the new directions for future understanding breast cancer therapy.

Epigenetic changes around the pX region and spontaneous HTLV-1 transcription are CTCF-independent.

Background: The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and minus-strands of the provirus are transcribed, respectively from the 5' and 3' long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF. Methods: Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax + and Tax - populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications. Results: Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3' LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications. Conclusions: The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.

Epigenetic changes around the pX region and spontaneous HTLV-1 transcription are CTCF-independent

Background: The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and minus-strands of the provirus are transcribed, respectively from the 5′ and 3′ long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF. Methods: Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax + and Tax – populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications. Results: Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3′ LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications. Conclusions: The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.

Genome-Wide DNA Methylation Analysis during Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells.

Bone marrow mesenchymal stem cells (BMSCs) nowadays are regarded as promising candidates in cell-based therapy for the regeneration of damaged bone tissues that are either incurable or intractable due to the insufficiency of current therapies. Recent studies suggest that BMSCs differentiate into osteoblasts, and that this differentiation is regulated by some specific patterns of epigenetic modifications, such as DNA methylation. However, the potential role of DNA methylation modification in BMSC osteogenic differentiation is unclear. In this study, we performed a genome-wide study of DNA methylation between the noninduced and induced osteogenic differentiation of BMSCs at day 7. We found that the majority of cytosines in a CpG context were methylated in induced BMSCs. Our results also revealed that, along with the induced osteogenic differentiation in BMSCs, the average genomic methylation levels and CpG methylation in transcriptional factor regions (TFs) were increased, the CpG methylation level of various genomic elements was mainly in the medium-high methylation section, and CpG methylation levels in the repeat element had highly methylated levels. The GO analysis of differentially methylated region- (DMR-) associated genes (DMGs) showed that GO terms, including cytoskeletal protein binding (included in Molecular Function GO terms), skeletal development (included in Biological Process GO terms), mesenchymal cell differentiation (included in Biological Process GO terms), and stem cell differentiation (included in Biological Process), were enriched in the hypermethylated DMGs. Then, the KEGG analysis results showed that the WNT pathway, inositol phosphate metabolism pathway, and cocaine addiction pathway were more correlative with the DMRs during the induced osteogenic differentiation in BMSCs. In conclusion, this study revealed the difference of methylated levels during the noninduced and induced osteogenic differentiation of BMSCs and provided useful information for future works to characterize the important function of epigenetic mechanisms on BMSCs' differentiation.

Spontaneous HTLV-1 transcription is accompanied by distinct epigenetic changes in the 5′ and 3′ long terminal repeats

Background:The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and minus-strands of the provirus are transcribed, respectively from the 5′ and 3′ long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF.Methods:Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax+and Tax–populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications.Results:Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3′ LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications.Conclusions:The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.

Abstract 3112: Distinct oncogenic events induce different DNA methylation and copy number changes in human mammary epithelial cells

Abstract Gene expression differences, combined with distinct patterns of genomic rearrangements and epigenetic modifications constitute the bases of molecular classification of breast cancer. Molecular subtypes may originate from different cell lineages in the mammary gland, but also from the early activation of oncogenes that may drive the establishment of these molecular subtypes. However, in the natural history of human cancer, it is difficult to discriminate between these two factors : cell lineage and initial oncogenic alterations. In this work, we designed an experimental strategy aiming at determining whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. We show that initial activation of CCNE1, WNT1 and RASv12 in shp53 immortalized HMECs results in different and reproducible profiles of mRNA and miR expression, copy number alterations (CNA) and DNA methylation modifications. Interestingly, first the extend of CNA measured as fraction of the genome altered was lower in HMECs transformed by RAS than CCNE1 and WNT1 transformed HMECs revealing a lower genetic instability. This was confirmed by less numerous γH2Ax and 53BP1 nuclear foci in HMECs transformed by RAS. Second, HMECs transformed by RAS bore specific profiles of CNAs and DNA methylation, clearly distinct of those shown by CCNE1 and WNT1 transformed HMECs. Genes differentially expressed in the RAS and the CCNE1/WNT1 clusters and included in CNAs or with variable CpG methylation were mostly different, depicting the activation of distinct signaling pathways in these two clusters. These data indicate that early activation of distinct oncogenic pathways may leads to adaptive events resulting in specific pattern of CNAs and DNA methylation changes. We postulated that the early activation of oncogenes may be an important determinant of the establishment of breast cancer molecular subtypes along with cell lineage origin. Citation Format: Stan P. du manoir, Claire Fonti, Anne Saumet, Amanda Abi-Khalil, Béatrice Orsetti, Cleroux Elouan, Ambre Bender, Michael Dumas, Jacques Colinge, Michael Weber, Charles Theillet. Distinct oncogenic events induce different DNA methylation and copy number changes in human mammary epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3112.

Elevated histone H3 acetylation is associated with genes involved in T lymphocyte activation and glutamate decarboxylase antibody production in patients with type 1 diabetes.

Aims/IntroductionGenetic and epigenetic mechanisms have been implicated in the pathogenesis of type 1 diabetes, and histone acetylation is an epigenetic modification pattern that activates gene transcription. However, the genome‐wide histone H3 acetylation in new‐onset type 1 diabetes patients has not been well described. Accordingly, we aimed to unveil the genome‐wide promoter acetylation profile in CD4+ T lymphocytes from type 1 diabetes patients, especially for those who are glutamate decarboxylase antibody‐positive.Materials and MethodsA total of 12 patients with new‐onset type 1 diabetes who were glutamate decarboxylase antibody‐positive were enrolled, and 12 healthy individuals were recruited as controls. The global histone H3 acetylation level of CD4+ T lymphocytes from peripheral blood was detected by western blot, with chromatin immunoprecipitation linked to microarrays to characterize the promoter acetylation profile. Furthermore, we validated the results of particular genes from chromatin immunoprecipitation linked to microarrays by using chromatin immunoprecipitation quantitative polymerase chain reaction, and analyzed the transcription level by real‐time quantitative polymerase chain reaction.ResultsElevated global histone H3 acetylation level was observed in type 1 diabetes patients, with 607 differentially acetylated genes identified between type 1 diabetes patients and controls by chromatin immunoprecipitation linked to microarrays. The hyperacetylated genes were enriched in biological processes involved in immune cell activation and inflammatory response. Gene‐specific assessments showed that increased transcription of inducible T‐cell costimulator was in concordance with the elevated acetylation in its gene promoter, along with positive correlation with glutamate decarboxylase antibody titer in type 1 diabetes patients.ConclusionsThe present study generates a genome‐wide histone acetylation profile specific to CD4+ T lymphocytes in type 1 diabetes patients who are glutamic acid decarboxylase antibody‐positive, which is instrumental in improving our understanding of the epigenetic involvement in autoimmune diabetes.

Genome‐Wide Analysis of Bromodomain Histone Di‐Acetyllysine Ligands

Combinatorial patterns of epigenetic modifications on core histone proteins serve in the marking of genomic elements for the recruitment of regulatory proteins to effect critical biological functions. The recognition of acetylated histone lysine residues by bromodomain chromatin readers appears to be an essential cellular mechanism that regulates protein‐protein interactions, chromatin remodeling, and gene expression. However, the functional relevance of the association of bromodomain chromatin readers and their genome‐wide association with various combinations of histone acetylations remains poorly understood. ATAD2 is a bromodomain‐containing protein highly overexpressed in solid tumors, and has been correlated to an increased risk of cancer metastasis and recurrence. ATAD2B (KIAA1240) is a poorly studied paralog of the ATAD2 gene, and although ATAD2 and ATAD2B are highly conserved, there is little known about the function of ATAD2B. In vitro binding assays demonstrate ATAD2 and ATAD2B bromodomains selectively recognize H4K5/H4K12 and H4K5/H4K8 di‐acetyllysine marks, respectively. To study the genome‐wide patterns of ATAD2/2B histone ligands, we used a Chromatin Immunoprecipitation followed by high‐throughput sequencing (ChIP‐seq) assay to characterize the genomic distribution of H4 tail lysine acetylation patterns in MCF7 breast cancer cells. We performed replicate H4K5, H4K8, H4K12 ChIP‐seq assays as well as H4K5/K8 or H4K5/K12 sequential ChIP‐seq assays. We provide a high‐resolution map of combinations of histone tail acetylation in MCF7 cells. Our results reveal unique patterns of chromatin states, genes and putative transcription factor binding sites associated with different combinations of diacetyllysine residues. Ongoing work seeks to define the recruitment of ATAD2/B, as well as other chromatin effector proteins, and to understand the functional relevance of histone ligand recognition on breast cancer cell gene expression programs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gene regulatory mechanisms underlying sex differences in brain development and psychiatric disease.

The sexual differentiation of the mammalian nervous system requires the precise coordination of the temporal and spatial regulation of gene expression in diverse cell types. Sex hormones act at multiple developmental time points to specify sex-typical differentiation during embryonic and early development and to coordinate subsequent responses to gonadal hormones later in life by establishing sex-typical patterns of epigenetic modifications across the genome. Thus, mutations associated with neuropsychiatric conditions may result in sexually dimorphic symptoms by acting on different neural substrates or chromatin landscapes in males and females. Finally, as stress hormone signaling may directly alter the molecular machinery that interacts with sex hormone receptors to regulate gene expression, the contribution of chronic stress to the pathogenesis or presentation of mental illness may be additionally different between the sexes. Here, we review the mechanisms that contribute to sexual differentiation in the mammalian nervous system and consider some of the implications of these processes for sex differences in neuropsychiatric conditions.

Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude.

TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.

Hypermethylation of Synphilin-1, Alpha-Synuclein-Interacting Protein (SNCAIP) Gene in the Cerebral Cortex of Patients with Sporadic Parkinson's Disease.

Objective: To determine and compare DNA methylation patterns between patients with Parkinson’s disease (PD) and age- and sex-similar matched non-PD controls. Background: Epigenetic regulation is one of the major mechanisms for an organism to respond to the environment through changes in gene expression and has been implicated in numerous disease processes. We would like to examine epigenetic modification patterns that may predispose or protect against PD. Methods: Frozen tissue samples of the human cerebral cortex from 12 PD patients and 12 subjects without PD pathology were obtained. Genome-wide DNA methylation profiling was performed using the Illumina HumanMethylation450 BeadChip array. Differential methylation was defined as a mean methylation level difference (delta β) of at least 0.20 (Δβ ≥ 0.20). Methylation regions with an absolute delta β value ≥ 0.20 were selected for further gene function studies. Results: We identified 2795 differentially methylated CpG sites in the frontal cortex of PD cases with a detection p-value of ≤ 0.01 and 328 differentially methylated CpG sites with a detection p-value of ≤ 0.001. A pattern of robust hypermethylation of synphilin-1, α-synuclein-interacting protein (SNCAIP) gene was found in the brain of PD cases (p = 4.93 × 10−7 and delta β = 0.60). Conclusion: Our findings support a link between SNCAIP methylation and PD risk. Hypomethylation of SNCAIP may function to protect against PD. The current results may suggest that the methylation status of SNCAIP could be useful as a marker in PD diagnosis and treatment and warrants further investigation.

Epigenetic memory in response to environmental stressors

Exposure to environmental stressors, toxicants, and nutrient deficiencies can affect DNA in several ways. Some exposures cause damage and alter the structure of DNA, but there is increasing evidence that the same or other environmental exposures, including those that occur during fetal development in utero, can cause epigenetic effects that modulate DNA function and gene expression. Some epigenetic changes to DNA that affect gene transcription are at least partially reversible (i.e., they can be enzymatically reversed after cessation of exposure to environmental agents), but some epigenetic modifications seem to persist, even for decades. To explain the effects of early life experiences (such as famine and exposures to other stressors) on the long-term persistence of specific patterns of epigenetic modifications, such as DNA methylation, we propose an analogy with immune memory. We propose that an epigenetic memory can be established and maintained in self-renewing stem cell compartments. We suggest that the observations on early life effects on adult diseases and the persistence of methylation changes in smokers support our hypothesis, for which a mechanistic basis, however, needs to be further clarified. We outline a new model based on methylation changes. Although these changes seem to be mainly adaptive, they are also implicated in the pathogenesis and onset of diseases, depending on individual genotypic background and types of subsequent exposures. Elucidating the relationships between the adaptive and maladaptive consequences of the epigenetic modifications that result from complex environmental exposures is a major challenge for current and future research in epigenetics.-Vineis, P., Chatziioannou, A., Cunliffe, V. T., Flanagan, J. M., Hanson, M., Kirsch-Volders, M., Kyrtopoulos, S. Epigenetic memory in response to environmental stressors.

Mechanisms of Brain Glucocorticoid Resistance in Stress-Induced Psychopathologies.

Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stress- and GR-induced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.

Epigenetic: A new approach to etiology of infertility

Infertility is a complex disease which could be caused by male and female factors. The etiology from both factors needs further study. There are some approaches to understanding the etiology of infertility, one of them is epigenetic. Epigenetic modifications consist of DNA methylation, histone modifications, and chromatin remodelling. Male and female germinal cells undergo epigenetic modifications dynamically during differentiation into matured sperm and oocyte cells. In a male, the alteration of DNA methylation in spermatogenesis will cause oligo/asthenozoospermia. In addition, the histone methylation, acetylation, or other histone modification may lead sperm lose its ability to fertilize oocyte. Similarly, in a female, the alteration of DNA methylation and histone modification affects oogenesis, created aneuploidy in fertilized oocytes and resulted in embryonic death in the uterus. Alteration of these epigenetic modification patterns will cause infertility, both in male and female.