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Distinguishing epigenetic marks of developmental and imprinting regulation
Kirsten R McEwen, Anne C Ferguson-Smith
Epigenetics & Chromatin , 2010, DOI: 10.1186/1756-8935-3-2
Abstract: Using high-throughput data extraction with subsequent analysis, we have found that particular histone modifications are more likely to be associated with either imprinting repression or developmental repression of imprinted genes. H3K9me3 and H4K20me3 are together enriched at imprinted genes with differentially methylated promoters and do not show a correlation with developmental regulation. H3K27me3 and H3K4me3, however, are more often associated with developmental regulation. We find that imprinted genes are subject to developmental regulation through bivalency with H3K4me3 and H3K27me3 enrichment on the same allele. Furthermore, a specific tri-mark signature comprising H3K4me3, H3K9me3 and H4K20me3 has been identified at all imprinting control regions.A large amount of data is produced from whole-genome expression and epigenetic profiling studies of cellular material. We have shown that such publicly available data can be mined and analysed in order to generate novel findings for categories of genes or regulatory elements. Comparing two types of gene regulation, imprinting and developmental, our results suggest that different histone modifications associate with these distinct processes. This form of analysis is therefore a useful tool to elucidate the complex epigenetic code associated with genome function and to determine the underlying features conferring epigenetic states.Epigenetic mechanisms play an important role in the control of gene expression. Modification to the packaging of DNA is believed to allow a more open or closed structure and influences association of the transcriptional machinery with the genetic material. The most characterised examples of epigenetic mechanisms to date in mammalian cells include DNA methylation of cytosine and post-translational modifications to the core histone proteins of the nucleosome (reviewed in [1]), though other epigenetic mechanisms are known to exist. Nevertheless, little is known regarding exactly how these two p
Identification of Genetic and Epigenetic Marks Involved in Population Structure  [PDF]
Jingyu Liu,Kent Hutchison,Nora Perrone-Bizzozero,Marilee Morgan,Jing Sui,Vince Calhoun
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013209
Abstract: Population structure is well known as a prevalent and important factor in genetic studies, but its relevance in epigenetics is unclear. Very little is known about the affected epigenetic markers and their connections with genetics. In this study we assessed the impact of population diversity on genome wide single nucleotide polymorphisms (SNPs) and DNA methylation levels in 196 participants from five ethnic groups, using principle and independent component analyses. Three population stratification factors (PSFs) were identified in the genomic SNP dataset, accounting for a relatively large portion of total variance (6%). In contrast, only one PSF was identified in genomic methylation dataset accounting for 0.2% of total variance. This methylation PSF, however, was significantly correlated with the largest SNP PSF (r = 0.72, p<1E-23). We then investigated the top contributing markers in these two linked PSFs. The SNP PSF predominantly consists of 8 SNPs from three genes, SLC45A2, HERC2 and CTNNA2, known to encode skin/hair/eye color. The methylation PSF includes 48 methylated sites in 44 genes coding for basic molecular functions, including transcription regulation, DNA binding, cytokine, and transferase activity. Among them, 8 sites are either hypo- or hyper-methylated correlating to minor alleles of SNPs in the SNP PSF. We found that the genes in SNP and methylation PSFs share common biological processes including sexual/multicellular organism reproduction, cell-cell signaling and cytoskeleton organization. We further investigated the transcription regulatory network operating at these genes and identified that most of genes closely interact with ID2, which encodes for a helix-loop-helix inhibitor of DNA binding. Overall, our results show a significant correlation between genetic and epigenetic population stratification, and suggest that the interrelationship between genetic and epigenetic population structure is mediated via complex multiple gene interactions in shared biological processes, through possibly, SNP-dependent modulation and ID2 repressor function.
Identifying Positioned Nucleosomes with Epigenetic Marks in Human from ChIP-Seq
Yong Zhang, Hyunjin Shin, Jun S Song, Ying Lei, X Shirley Liu
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-537
Abstract: This paper describes a novel computational framework to efficiently identify positioned nucleosomes and their histone modification profiles from nucleosome-resolution histone modification ChIP-Seq data. We applied the algorithm to histone methylation ChIP-Seq data in human CD4+ T cells and identified over 438,000 positioned nucleosomes, which appear predominantly at functionally important regions such as genes, promoters, DNase I hypersensitive regions, and transcription factor binding sites. Our analysis shows the identified nucleosomes play a key role in epigenetic gene regulation within those functionally important regions via their positioning and histone modifications.Our method provides an effective framework for studying nucleosome positioning and epigenetic marks in mammalian genomes. The algorithm is open source and available at http://liulab.dfci.harvard.edu/NPS/ webcite.Chromatin structure widely manifests itself in various aspects of mammalian development and disease. The key structural element of chromatin is the nucleosome, which consists of an octameric histone core wrapped by 146 bps of DNA [1]. Nucleosomes play two major roles in epigenetic regulation of gene expression. The first is to limit DNA accessibility to cellular machinery [2-5] through specific positioning of nucleosome core particles, which can be remodeled in an ATP-dependent manner. The second is to regulate transcriptional activities through covalent modifications (e.g. methylation, acetylation and phosphorylation) of the tails of four core histone types H2A, H2B, H3 and H4 [6-9]. Therefore, characterizing the global locations and modification marks of positioned nucleosomes is a crucial step towards unraveling the mechanism of epigenetic regulation in eukaryotes.High-throughput mapping of positioned nucleosomes has been conducted in yeast [10,11] and selected human promoters [12] using high resolution tiling microarrays. Several studies have also profiled genome-scale histone modifica
In Search of Epigenetic Marks in Testes and Sperm Cells of Differentially Fed Boars  [PDF]
Rémy Bruggmann, Vidhya Jagannathan, Martin Braunschweig
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078691
Abstract: In search of transmittable epigenetic marks we investigated gene expression in testes and sperm cells of differentially fed F0 boars from a three generation pig feeding experiment that showed phenotypic differences in the F2 generation. RNA samples from 8 testes of boars that received either a diet enriched in methylating micronutrients or a control diet were analyzed by microarray analysis. We found moderate differential expression between testes of differentially fed boars with a high FDR of 0.82 indicating that most of the differentially expressed genes were false positives. Nevertheless, we performed a pathway analysis and found disparate pathway maps of development_A2B receptor: action via G-protein alpha s, cell adhesion_Tight junctions and cell adhesion_Endothelial cell contacts by junctional mechanisms which show inconclusive relation to epigenetic inheritance. Four RNA samples from sperm cells of these differentially fed boars were analyzed by RNA-Seq methodology. We found no differential gene expression in sperm cells of the two groups (adjusted P-value>0.05). Nevertheless, we also explored gene expression in sperm by a pathway analysis showing that genes were enriched for the pathway maps of bacterial infections in cystic fibrosis (CF) airways, glycolysis and gluconeogenesis p.3 and cell cycle_Initiation of mitosis. Again, these pathway maps are miscellaneous without an obvious relationship to epigenetic inheritance. It is concluded that the methylating micronutrients moderately if at all affects RNA expression in testes of differentially fed boars. Furthermore, gene expression in sperm cells is not significantly affected by extensive supplementation of methylating micronutrients and thus RNA molecules could not be established as the epigenetic mark in this feeding experiment.
Hypermethylation Status of Promoter is an Epigenetic Change in Lymphoied Malignancies
Majid Farshdousti Hagh,Najmaldin Saki,Gholamreza Khamisipour
International Journal of Hematology-Oncology and Stem Cell Research , 2012,
Abstract: Alteration in methylation pattern of promoters is associated with tumorigenic events,(1, 2) and differentiation control,(3, 4) in several types of cells in humans. Specific hypermethylation in promoter region of some genes exist in different types of neoplastic cells.(5) DNA methylation indicates to the addition of a methyl moiety to the cytosine in a CpG dinucleotide. CpG dinucleotides tend to gather closely together in CpG islands, and are usually located in promoter region of genes.(6) In cancerous transformation, there is a change in the methylation pattern of specific genes, by which hypermethylation of CpG islands in promoter region and hypomethylation of the noncoding regions occur.(7) Methylation of CpG islands in promoter region result in gene silencing, a phenomenon that has oncogenic potential when it arises in tumor suppressor genes. The methylation status of several promoters has been analyzed in lymphoid malignancies. Roman-Gomez et al. evaluate the 39 genes involved in cell immortalization and transformation in 307 patients with acute lymphoblastic leukemia (ALL) by Methylation Specific PCR (MSP). Of 39 genes 23 genes showed hypermethylation status in promoter region of genes including: SMC1L2, NES1, ADAMTS1, PGR, sFRP1, CDH1, ADAMTS5, CDH13, LATS1, DKK3, WIF1, LATS2, REPRIMO, sFRP5, PARK2, PACRG, HDPR1, RIZ, APAF1, ARTS, ASPP1, DIABLO and sFRP4.(8) Dunwell et al. demonstrated frequent epigenetic inactivation of THRB, BNC1, PPP2R3A, FBLN2 and MSX1 in lymphoied malignancies including B-cell and T-cell ALL.(9) The recognition of hypermethylated genes in lymphoid malignancies showing epigenetic alterations will be useful in developing targeted epigenetic therapies.(10, 11, 12) Also, Methylation changes of CpG islands in promoter region of the p57KIP2, p73, and p15 genes have been shown to have poor prognostic value in adult ALL patients with Philadelphia (Ph) chromosome-negative disease.(13) These methylation changes are stable in greater number of patients with ALL at the time of relapse. Therefore, they can be used as a marker for minimal residual disease (MDR) detection.(14) Hence, epigenetic mechanism such as hypermethylation in promoter region of genes can play important role in pathogenesis, diagnosis, prognosis, relapse detection and therapy of ALL. Nonetheless other epigenetic mechanisms such as histone modifications and small non coding RNAs such as microRNAs may have role in lymphoid malignancies.
Search for Conditions to Detect Epigenetic Marks and Nuclear Proteins in Immunostaining of the Testis and Cartilage  [PDF]
Hisashi Ideno,Akemi Shimada,Taichi Kamiunten,Kazuhiko Imaizumi,Yoshiki Nakamura,Hiroshi Kimura,Ryoko Araki,Masumi Abe,Kazuhisa Nakashima,Akira Nifuji
Journal of Histology , 2014, DOI: 10.1155/2014/658293
Abstract: The localization of nuclear proteins and modified histone tails changes during cell differentiation at the tissue as well as at the cellular level. Immunostaining in paraffin sections is the most powerful approach available to evaluate protein localization. Since nuclear proteins are sensitive to fixation, immunohistochemical conditions should be optimized in light of the particular antibodies and tissues employed. In this study, we searched for optimal conditions to detect histone modification at histone H3 lysine 9 (H3K9) and H3K9 methyltransferase G9a in the testis and cartilage in paraffin sections. In the testis, antigen retrieval (AR) was indispensable for detecting H3K9me1 and me3, G9a, and nuclear protein proliferating cell nuclear antigen (PCNA). With AR, shorter fixation times yielded better results for the detection of G9a and PCNA. Without AR, H3K9me2 and H3K9ac could be detected at shorter fixation times in primary spermatocytes of the testis. In contrast to the testis, all antibodies tested could detect their epitopes irrespective of AR application in the growth plate cartilage. Thus, conditions for the detection of epigenetic marks and nuclear proteins should be optimized in consideration of fixation time and AR application in different tissues and antibodies. 1. Introduction Tissue-specific factors are expressed exclusively in certain groups of cells during cellular differentiation and cell fate determination. Genes activated during differentiation are maintained in a transcriptionally competent state in chromatin, whereas genes that are not activated in a given lineage are maintained in a silenced state. The transcriptionally competent state is characterized by an open chromatin locus, which is accessible to tissue-specific factors. In a silenced state, transcriptionally inactive condensed chromatin is formed [1–3]. Open or closed chromatin structures are characterized by the acetylation or methylation of histone tails, which are referred to as epigenetic marks, as well as chromatin-modifying nuclear proteins [4–6]. The modifications of histone tails are regulated by histone modification enzymes. For example, there are four methylated states at lysine 9 of histone H3: non-, mono-, di-, and trimethylated H3K9. These methylated states are determined by the balance of methyltransferases and demethylases. The key histone methyltransferases is G9a, which is a member of the Suv39h subgroup of SET domain-containing molecules [7]. G9a is responsible for the modification of H3K9me1 and H3K9me2, and affects chromatin status, leading to gene
Epigenetic changes in the estrogen receptor α gene promoter: implications in sociosexual behaviors  [PDF]
Ken Ichi Matsuda
Frontiers in Neuroscience , 2014, DOI: 10.3389/fnins.2014.00344
Abstract: Estrogen action through estrogen receptor α (ERα) is involved in the control of sexual and social behaviors in adult mammals. Alteration of ERα gene activity mediated by epigenetic mechanisms, such as histone modifications and DNA methylation, in particular brain areas appears to be crucial for determining the extents of these behaviors between the sexes and among individuals within the same sex. This review provides a summary of the epigenetic changes in the ERα gene promoter that correlate with sociosexual behaviors.
The Role of Multiple Marks in Epigenetic Silencing and the Emergence of a Stable Bivalent Chromatin State  [PDF]
Swagatam Mukhopadhyay ,Anirvan M. Sengupta
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003121
Abstract: We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.
Epigenetic Changes in Response to Tai Chi Practice: A Pilot Investigation of DNA Methylation Marks
Hua Ren,Veronica Collins,Sandy J. Clarke,Jin-Song Han,Paul Lam,Fiona Clay,Lara M. Williamson,K. H. Andy Choo
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/841810
Abstract: Tai chi exercise has been shown to improve physiological and psychosocial functions, well-being, quality of life, and disease conditions. The biological mechanisms by which tai chi exerts its holistic effects remain unknown. We investigated whether tai chi practice results in positive epigenetic changes at the molecular level. Design. The DNA methylation profiles of sixty CpG-dinucleotide marks in female tai chi practitioners (=237; 45–88 years old) who have been practising tai chi for three or more years were compared with those of age-matched control females (=263) who have never practised tai chi. Results. Six CpG marks originating from three different chromosomes reveal a significant difference (<0.05) between the two cohorts. Four marks show losses while two marks show gains in DNA methylation with age in the controls. In the tai chi cohort all six marks demonstrate significant slowing (by 5–70%) of the age-related methylation losses or gains observed in the controls, suggesting that tai chi practice may be associated with measurable beneficial epigenetic changes. Conclusions. The results implicate the potential use of DNA methylation as an epigenetic biomarker to better understand the biological mechanisms and the health and therapeutic efficacies of tai chi.
CTCF Prevents the Epigenetic Drift of EBV Latency Promoter Qp  [PDF]
Italo Tempera,Andreas Wiedmer,Jayaraju Dheekollu,Paul M. Lieberman
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001048
Abstract: The establishment and maintenance of Epstein-Barr Virus (EBV) latent infection requires distinct viral gene expression programs. These gene expression programs, termed latency types, are determined largely by promoter selection, and controlled through the interplay between cell-type specific transcription factors, chromatin structure, and epigenetic modifications. We used a genome-wide chromatin-immunoprecipitation (ChIP) assay to identify epigenetic modifications that correlate with different latency types. We found that the chromatin insulator protein CTCF binds at several key regulatory nodes in the EBV genome and may compartmentalize epigenetic modifications across the viral genome. Highly enriched CTCF binding sites were identified at the promoter regions upstream of Cp, Wp, EBERs, and Qp. Since Qp is essential for long-term maintenance of viral genomes in type I latency and epithelial cell infections, we focused on the role of CTCF in regulating Qp. Purified CTCF bound ~40 bp upstream of the EBNA1 binding sites located at +10 bp relative to the transcriptional initiation site at Qp. Mutagenesis of the CTCF binding site in EBV bacmids resulted in a decrease in the recovery of stable hygromycin-resistant episomes in 293 cells. EBV lacking the Qp CTCF site showed a decrease in Qp transcription initiation and a corresponding increase in Cp and Fp promoter utilization at 8 weeks post-transfection. However, by 16 weeks post-transfection, bacmids lacking CTCF sites had no detectable Qp transcription and showed high levels of histone H3 K9 methylation and CpG DNA methylation at the Qp initiation site. These findings provide direct genetic evidence that CTCF functions as a chromatin insulator that prevents the promiscuous transcription of surrounding genes and blocks the epigenetic silencing of an essential promoter, Qp, during EBV latent infection.
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