epigenetics
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Mice Inherit Specific Memories, Because Epigenetics?

Mice Inherit Specific Memories, Because Epigenetics? | epigenetics | Scoop.it
Two weeks ago I wrote about some tantalizing research coming out of the Society for Neuroscience meeting in San Diego. Brian Dias, a postdoctoral fellow in Kerry Ressler's lab at Emory University, ...
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Low relative humidity triggers RNA-directed de novo DNA methylation and suppression of genes controlling stomatal development (J Exp Bot)

Low relative humidity triggers RNA-directed de novo DNA methylation and suppression of genes controlling stomatal development (J Exp Bot) | epigenetics | Scoop.it

Environmental cues influence the development of stomata on the leaf epidermis, and allow plants to exert plasticity in leaf stomatal abundance in response to the prevailing growing conditions. It is reported that Arabidopsis thaliana ‘Landsberg erecta’ plants grown under low relative humidity have a reduced stomatal index and that two genes in the stomatal development pathway, SPEECHLESS and FAMA, become de novo cytosine methylated and transcriptionally repressed. These environmentally-induced epigenetic responses were abolished in mutants lacking the capacity for de novo DNA methylation, for the maintenance of CG methylation, and in mutants for the production of short-interfering non-coding RNAs (siRNAs) in the RNA-directed DNA methylation pathway. Induction of methylation was quantitatively related to the induction of local siRNAs under low relative humidity. Our results indicate the involvement of both transcriptional and post-transcriptional gene suppression at these loci in response to environmental stress. Thus, in a physiologically important pathway, a targeted epigenetic response to a specific environmental stress is reported and several of its molecular, mechanistic components are described, providing a tractable platform for future epigenetics experiments. Our findings suggest epigenetic regulation of stomatal development that allows for anatomical and phenotypic plasticity, and may help to explain at least some of the plant’s resilience to fluctuating relative humidity.


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Transgenerational epigenetic instability is a source of novel methylation variants (Science)

Transgenerational epigenetic instability is a source of novel methylation variants (Science) | epigenetics | Scoop.it

Epigenetic information, which may affect an organism's phenotype, can be stored and stably inherited in the form of cytosine DNA methylation. Changes in DNA methylation can produce meiotically stable epialleles that affect transcription and morphology, but the rates of spontaneous gain or loss of DNA methylation are unknown. We examined spontaneously occurring variation in DNA methylation in Arabidopsis thaliana plants propagated by single-seed descent for 30 generations. 114,287 CG single methylation polymorphisms (SMPs) and 2485 CG differentially methylated regions (DMRs) were identified, both of which show patterns of divergence compared to the ancestral state. Thus, transgenerational epigenetic variation in DNA methylation may generate new allelic states that alter transcription, providing a mechanism for phenotypic diversity in the absence of genetic mutation.


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DNA methylation age of human tissues and cell types

Background:
It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure.

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Schizophrenia Diagnosis Via Epigenetic Changes In Blood

Schizophrenia Diagnosis Via Epigenetic Changes In Blood | epigenetics | Scoop.it
In a new study, researchers at the Swedish medical university Karolinska Institutet have identified epigenetic changes - known as DNA methylation - in the blood of patients with schizophrenia.

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DNA Methylation

DNA Methylation | epigenetics | Scoop.it
What is DNA Methylation? . DNA methylation is a biochemical reaction that adds a methyl group to DNA nucleotides. The methylation of DNA has been found to alter the expression of genes in cells dur...

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G bouts's curator insight, June 20, 2014 3:41 PM

DNA Methylation
BY KLAUS D. LINSE on MAY 15, 2013 • ( 0 )
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What is DNA Methylation?

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DNA methylation is a biochemical reaction that adds a methyl group to DNA nucleotides. The methylation of DNA has been found to alter the expression of genes in cells during development.

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The DNA in higher eukaryotic cells is known to contain methylated cytosine residues. Most of these methylation sites are found within CG dinucleotides called CpG motifs or elements. The CpG sequence motif is sometimes also called a HTF island and is a classical genetic feature usually found associated with upstream sequence regions of transcriptionally active genes. HTF stands for “HpaII tiny fragments.”

Methylation of Cysteines

Overview of how methylation of cytosines influences biological processes.

The methyl group on cytosine can either directly or indirectly change the DNA biochemistry. The biochemical modifications can serve as molecular signals for chromosome functions. The resulting effects determine development, physiology, and pathology of an organism. (Source: Franchini et al. 2012).

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A HTF island is a tiny DNA fragment, approximately 1000-2000 base pairs long which is usually found associated with expressed genes and is characterized by the relatively rare CpG dinucleotide that occurs unmethylated. Digesting DNA with the restriction nuclease HpaII generates the fragment. For example, chromosome walking together with pulsed field gel electrophoresis allowed to verify the presence of clusters of CpG dinucleotides within the major histocompatibility complex (MHC) class III genomic region in the past and there characterization. These findings suggested that a number or multiples of HTF-islands can be present in genetic DNA regions. Scientists now know that CpG islands surround the promoters of housekeeping genes which encode enzymes involved in essential metabolic pathways such as glycolysis and others. There is increasing experimental evidence that indicate that the state of methylation of CpG islands affect the expression of genes. The recognition that the enzymatic methylation of the cytosine base plays a crucial role in the regulation of chromatin stability, gene regulation, parental imprinting, and X chromosome inactivation in females has led to the new scientific field of epigenetics.

Furthermore, the findings that erroneous DNA methylation may lead to cancer, other diseases and is involved in the aging process suggests that this type of methylation is a major important regulatory epigenetic event. Therefore we can conclude that the analysis of the cytosine methylation status is of great importance for our understanding of gene expression and regulation mechanisms.

Structures of cytosine and 5-methylcytosine.

C a mC

The cytosine is methylated at the C5 position: Note that the addition of a methylgroup to the cytosine increases the mass of the base by 14.01565 mass units (Da).

The methylation of the cytosine base on the C5 position was the first identified modification of DNA. This type of methylation has been intensively investigated during the last 40 to 50 years and it has now become clear that the major eukaryotic DNA methyl-transferase, Dnmt1, accurately maintains genome-wide methylation patterns and plays an essential role in the epigenetic network that controls gene expression and genome stability during cellular development. The family of DNA methyltransferases (DNA MTase) catalyzes the transfer of a methyl group to DNA bases such as cytosine. DNA methylation has now been identified in a wide variety of biological functions. The methyl-group donor S-adenosyl methionine (SAM) is the donor for all the known DNA methyltransferases.

DNA methylation 1The DNA methyltransferase (DNMT) uses S-adenosylmethionine (SAM) as the methyl donor. S-adenosylhomocysteine (SAH) is the leaving molecule which acts as an inhibitor of the transferase. The methylation metabolism converts SAH back to SAM. DNMT can copy methylation patterns from one strand of double stranded DNA (dsDNA) to the complementary strand thereby maintaining methylation pattern. However, DNMT can also create new methylation patterns. In general, methylation patterns are well maintained in stable differentiated cells in vivo.

SAM (S-adenosylmethionine,or AdoMet) is a methyl donor for many methyltransferases that modify DNA, RNA, histones and other substrates. It is an important cofactor involved in the transfer of a methyl group. The methyl group (CH3) attached to the methionine sulfur atom in SAM is chemically reactive which allows the donation of this group to acceptor molecules. The molecule was first discovered by G. L. Cantoni in Italy in 1952. It is synthesized from adenosine triphosphate (ATP) and methionine by the enzyme methionine adenosyltransferase (EC 2.5.1.6). Most SAM is produced and consumed in the liver.

Many metabolic reactions involve the transfer of a methyl group from SAM to various substrates, such as nucleic acids, proteins, lipids and secondary metabolites. The compound S-Adenosyl-L-homocysteine (SAH) is generated by the demethylation of SAM during the methyl group transfer reaction as shown in the figure below.

SAM t SAHAll these molecules are part of the genetic mechanisms that control replication, transcription and translation fidelity, and are involved in nucleotide pair mismatch repair, chromatin remodeling, epigenetic modifications and imprinting. Furthermore, these are topics of great interest and importance in cancer research and aging.

CpG islands are involved in gene silencing. It has been found that the methylation of CpG islands in the promoter region of a gene inactivates the gene. The de-methylation of CpG islands in the promoter region of a gene activates the gene. Misregulation of this mechanism in tissue and cells has been implicated to initiate cancer in humans.

The crystal structure of HaeIII methyltransferase convalently complexed to DNA was solved by Reinisch et al in 1995. It revealed the location of the extrahelical cytosine and the rearrangement of DNA base pairing within the active site of the protein.

HaeIII Methyltransferase structure

Structure of the HaeIII Methyltransferase, MMDB ID: 71850. PDB ID: 1DCT. This structural information provides detailed insights into the inner workings and possible regulation of this intriguing enzyme. (Left) The DNA double helix with the flipped out cytosine is shown. (Right) The DNA-enzyme complex is shown. The DNA duplex is bound so that the major groove faces the small and the minor groove faces the large enzyme domain. (Source: Reinisch et al. 1995). The following table lists the molecules and their interactions in the complex.

HaeIII Methyltransferase Interactions

(Source: Pubmed, Structure Database: MMDB ID: 71850. PDB ID: 1DCT)

Many organisms expand the information content of their genome through enzymatic methylation of cytosine residues. Reinisch et al in 1995 reported the 2.8 A crystal structure of a bacterial DNA (cytosine-5)-methyltransferase (DCMtase), M. HaeIII, bound covalently to DNA. The structure shows that in the complex, the substrate cytosine is flipped out from the DNA helix and inserted into the active site of the enzyme.The DNA is bound in a cleft between the two domains of the protein and is distorted from the characteristic B-form conformation at its recognition sequence. During the recognition process the remaining bases in its recognition sequence undergo an extensive rearrangement in their pairing in which the bases are unstacked, and a gap 8 Å long opens in the DNA.

More recently the multiple steps of the methyl transfer reaction have been worked out for the related prokaryotic enzymes in molecular detail. Takeshita et al. in 2011 solved the crystal structure of a mammalian Dnmt1 (mouse) that contained the complete catalytic domain and most of the N-terminal regulatory region. The structure revealed the spatial arrangement and possible functional interactions of Dnmt1 domains. The methylgroup transfer reaction involves the flipping out of the target cytosine of the DNA double helix followed by the formation of a covalent complex with the C6 cytosine position to activate the C5 position for transfer of the methyl group from SAM. After that the enzyme is released by β-elimination and the methylated base is flipped back into the DNA double helix. To do this the enzyme requires the N-terminal region for activation. In vivo, Dnmt1 associates with the replication machinery via a PCNA-binding domain (PBD) and a targeting sequence mediates association with heterochromatin. The N-terminal target sequence (TS) was found to be inserted into the DNA-binding pocket of the catalytic domain. Complementary electrostatic surface potentials appear to anchor the TS domain in the catalytic DNA-binding pocket. This structure is further stabilized by specific hydrogen bonds. Furthermore, it was found that hydrophobic interactions between the peptide stretch, connecting the TS and the zinc finger (CXXC) domains, and the PCQ-loop at the catalytic center appear to stabilize the position of the TS domain by narrowing the entrance of the DNA-binding pocket. The PCQ loop appears to represent a sequence module for protein−DNA interactions found in methyltransferases.

Selected References

Don-Marc Franchini, Kerstin-Maike Schmitz, and Svend K. Petersen-Mahrt; 5-Methylcytosine DNA Demethylation: More Than Losing a Methyl Group. Annual reviews of genetics. Vol. 46: 419–441.

Carina Frauer and Heinrich Leonhardt; Twists and turns of DNA methylation PNAS 2011 ; published ahead of print May 18, 2011, doi:10.1073/pnas.1105804108.

Jamie A. Hackett, Roopsha Sengupta, Jan J. Zylicz, Kazuhiro Murakami, Caroline Lee, Thomas A. Down, M. Azim Surani; Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine. Science 25 January 2013: Vol. 339 no. 6118 pp. 448-452. DOI: 10.1126/science.1229277

Hussain Z, Khan MI, Shahid M, Almajhdi FN; S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer. Genet Mol Res. 2013 Apr 10;12(2):1106-18. doi: 10.4238/2013.April.10.6.

Reinisch KM, Che

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Recognition of methylated DNA by TAL effectors - Cell Research

Recognition of methylated DNA by TAL effectors - Cell Research | epigenetics | Scoop.it

Deng et al, 2012

Our experimental characterization provides a molecular basis for distinguishing methylated and unmethylated cytosine. Binding of mC by TALE repeat through the RVD NG extends the DNA recognition code and has potential application in epigenetics and cancer research. For example, specific TALE repeats may be designed to recognize the hypermethylated DNA region; detection can be facilitated by fusing TALEs with fluorescence proteins.
Our study also strongly argues that the in vivo methylation status of the target DNA sequence must be considered for the design of specific DNA-binding TALEs. Methylation of the base C in vivo might render the DNA sequence unfit for binding by the designed TALEs. Because the methylation status of DNA sequences is frequently under dynamic control, one would have to design at least two TALEs for one DNA sequence (i.e., one for methylated and one for unmethylated). In fact, assessment of methylation status of specific DNA sequences in vivo can be greatly facilitated through quantification of fluorescence signal of designed GFP-TALEs. Alternatively, the CpG sequences may be avoided for the application of TALEs, although this practice will somehow limit the potential application.
Despite these complexities, the discovery of mC binding by TALEs with RVD NG opens a number of exciting opportunities.


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The MASTER (methylation-assisted tailorable ends rational) ligation method for seamless DNA assembly

The MASTER (methylation-assisted tailorable ends rational) ligation method for seamless DNA assembly | epigenetics | Scoop.it

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Gerd Moe-Behrens's curator insight, February 28, 2013 4:02 PM

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Blätke MA, Dittrich A, Rohr C, Heiner M, Schaper F, Marwan W.

"Mathematical models of molecular networks regulating biological processes in cells or organisms are most frequently designed as sets of ordinary differential equations. Various modularisation methods have been applied to reduce the complexity of models, to analyse their structural properties, to separate biological processes, or to reuse model parts. Taking the JAK/STAT signalling pathway with the extensive combinatorial cross-talk of its components as a case study, we make a natural approach to modularisation by creating one module for each biomolecule. Each module consists of a Petri net and associated metadata and is organised in a database publically accessible through a web interface (). The Petri net describes the reaction mechanism of a given biomolecule and its functional interactions with other components including relevant conformational states. The database is designed to support the curation, documentation, version control, and update of individual modules, and to assist the user in automatically composing complex models from modules. Biomolecule centred modules, associated metadata, and database support together allow the automatic creation of models by considering differential gene expression in given cell types or under certain physiological conditions or states of disease. Modularity also facilitates exploring the consequences of alternative molecular mechanisms by comparative simulation of automatically created models even for users without mathematical skills. Models may be selectively executed as an ODE system, stochastic, or qualitative models or hybrid and exported in the SBML format. The fully automated generation of models of redesigned networks by metadata-guided modification of modules representing biomolecules with mutated function or specificity is proposed."

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Epigenetic and Genetic Influences on DNA Methylation Variation in Maize Populations

DNA methylation is a chromatin modification that is frequently associated with epigenetic regulation in plants and mammals. However, genetic changes such as transposon insertions can also lead to changes in DNA methylation. Genome-wide profiles of DNA methylation for 20 maize (Zea mays) inbred lines were used to discover differentially methylated regions (DMRs). The methylation level for each of these DMRs was also assayed in 31 additional maize or teosinte genotypes, resulting in the discovery of 1966 common DMRs and 1754 rare DMRs. Analysis of recombinant inbred lines provides evidence that the majority of DMRs are heritable. A local association scan found that nearly half of the DMRs with common variation are significantly associated with single nucleotide polymorphisms found within or near the DMR. Many of the DMRs that are significantly associated with local genetic variation are found near transposable elements that may contribute to the variation in DNA methylation. Analysis of gene expression in the same samples used for DNA methylation profiling identified over 300 genes with expression patterns that are significantly associated with DNA methylation variation. Collectively, our results suggest that DNA methylation variation is influenced by genetic and epigenetic changes that are often stably inherited and can influence the expression of nearby genes.


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Epigenetic discovery may yield cancer clues

Epigenetic discovery may yield cancer clues | epigenetics | Scoop.it

A new study finds the first link between the two most fundamental epigenetic tags—DNA methylation and histone modification—in humans.


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MLML: consistent simultaneous estimates of DNA methylation and hydroxymethylation

MLML: consistent simultaneous estimates of DNA methylation and hydroxymethylation | epigenetics | Scoop.it

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An Apple a Day Keeps the DNA Methylation Away! Vitamin C and DNA Demethylation in Mouse ES Cells - EpiBeat

An Apple a Day Keeps the DNA Methylation Away! Vitamin C and DNA Demethylation in Mouse ES Cells - EpiBeat | epigenetics | Scoop.it
DNA methylation is an epigenetic modification that is essential for normal development and also plays important roles in diverse cellular functions, such as genomic imprinting, X-chromosome inactivation, suppression of repetitive DNA elements,...

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History of parvovirus B19 infection is associated with a DNA methylation signature in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) likely has a multistep etiology, with initial genetic aberrations occurring early in life. An abnormal immune response to common infections has emerged as a plausible candidate for triggering the proliferation of pre-leukemic clones and the fixation of secondary genetic mutations and epigenetic alterations. We investigated whether evidence of infection with a specific common myelotropic childhood virus, parvovirus B19 (PVB19), relates to patterns of gene promoter DNA methylation in ALL patients. ...


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Epigenetics - Wikipedia

Epigenetics - Wikipedia, the free encyclopedia

In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity which are not caused by changes in the DNA sequence. Unlike simple genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes.

For the unfolding of an organism or the theory that plants and animals (including humans) develop in this way, see epigenesis (biology). For epigenetics in robotics, see developmental robotics.
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- (Greek: επί- over, above, outer) -genetics. It refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such changes are DNA methylation and histone deacetylation, both of which serve to suppress gene expression without altering the sequence of the silenced genes.


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A Prognostic DNA Methylation Signature for Stage I Non–Small-Cell Lung Cancer

A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.


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Cancer Commons's curator insight, October 1, 2013 3:43 PM

Sandoval J, Mendez-Gonzalez J, Nadal E, Chen G, et al. Journal of Clinical Oncology. Sept 30, 2013.

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DNMT1-Interacting RNAs Block Gene-Specific DNA Methylation

DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. 


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Cancer Commons's curator insight, October 10, 2013 6:07 PM

Ruscio AD, Ebralidze AK, Benoukraf T, Amabile G, et al. Nature. Oct 9, 2013.

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PLOS Genetics: A Pre-mRNA-Splicing Factor Is Required for RNA-Directed DNA Methylation in Arabidopsis

PLOS Genetics: A Pre-mRNA-Splicing Factor Is Required for RNA-Directed DNA Methylation in Arabidopsis | epigenetics | Scoop.it

"Small RNA expression analysis on loci showing RDM16-dependent DNA methylation suggested that unlike the previously reported putative splicing factor mutants, rdm16 did not affect small RNA levels; instead, the rdm16 mutation caused a decrease in the levels of Pol V transcripts. ChIP assays revealed that RDM16 was enriched at some Pol V target loci. Our results suggest that RDM16 regulates DNA methylation through influencing Pol V transcript levels."


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