From DNA to a human: What the ENCODE and Roadmap Epigenome Projects can teach us about how we are who we are

The assembly of the human genome sequence revealed that there are 3.2 billion bases in our genome, but what was less clear at the time was how this vast amount of information was organised and expressed to ensure that a single-celled zygote was able to develop into a fully functioning human body. The ENCODE project began the quest to identify and assign function to different elements within the genome and the Roadmap Epigenome Project has continued this journey by mapping chemical modifications such as DNA methylation, which are known to affect gene expression. Understanding these elements and processes in greater depth will allow us to learn more about how we became who we are and what differentiates humans from other animals.

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Concerted genomic and epigenomic changes accompany stabilization of Arabidopsis allopolyploids

Nature Ecology & Evolution ◽

10.1038/s41559-021-01523-y ◽

2021 ◽

Vol 5 (10) ◽

pp. 1382-1393

Author(s):

Xinyu Jiang ◽

Qingxin Song ◽

Wenxue Ye ◽

Z. Jeffrey Chen

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Small Rnas ◽

Structural Variation ◽

Self Incompatibility ◽

Polyploid Evolution ◽

Genomic Variations ◽

Conserved Gene ◽

Arabidopsis Suecica ◽

Affect Gene Expression

AbstractDuring evolution successful allopolyploids must overcome ‘genome shock’ between hybridizing species but the underlying process remains elusive. Here, we report concerted genomic and epigenomic changes in resynthesized and natural Arabidopsis suecica (TTAA) allotetraploids derived from Arabidopsisthaliana (TT) and Arabidopsisarenosa (AA). A. suecica shows conserved gene synteny and content with more gene family gain and loss in the A and T subgenomes than respective progenitors, although A. arenosa-derived subgenome has more structural variation and transposon distributions than A. thaliana-derived subgenome. These balanced genomic variations are accompanied by pervasive convergent and concerted changes in DNA methylation and gene expression among allotetraploids. The A subgenome is hypomethylated rapidly from F1 to resynthesized allotetraploids and convergently to the T-subgenome level in natural A. suecica, despite many other methylated loci being inherited from F1 to all allotetraploids. These changes in DNA methylation, including small RNAs, in allotetraploids may affect gene expression and phenotypic variation, including flowering, silencing of self-incompatibility and upregulation of meiosis- and mitosis-related genes. In conclusion, concerted genomic and epigenomic changes may improve stability and adaptation during polyploid evolution.

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Nutritional Influences on Epigenetics, Aging and Disease

The Indonesian Biomedical Journal ◽

10.18585/inabj.v11i1.780 ◽

2019 ◽

Vol 11 (1) ◽

pp. 16-29 ◽

Cited By ~ 1

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Critical Role ◽

Fumarate Hydratase ◽

Chemical Modifications ◽

Transcriptional Regulatory ◽

Nutritional Influences ◽

Nutrient Environment ◽

Epigenetic Gene Regulation ◽

Intracellular Metabolism

BACKGROUND: Altered epigenetics is regarded to play quite a role in many chronic diseases including cancer, diabetes, obesity, dyslipidemia, hypertension and neurodegeneration, hence nutrition suggested to contribute in epigenetics and disease.CONTENT: Histone modifications, as a part of epigenetics mechanisms, depend on metabolites which acts as cofactors or substrates. Fluctuating levels of specific metabolites become the direct and rapid mechanisms to influence gene activity. Therefore, these metabolites may have a role as gatekeepers of chromatin, in chromatin landscape modulation as a response to key nutritional cues. Chemical modifications of histones and DNA have a critical role in epigenetic gene regulation including histone acetylation, and DNA methylation. Some enzymes add or remove such chemical modifications, and suggested to be sensitive to changes in intracellular metabolism, such as mutations in the metabolic enzymes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) can result in cancer.SUMMARY: As a response to their nutrient environment, organisms tend to rapidly alter their gene expression. Many evidences showed an epigenetic regulation of chromatin is coupled to the changes on metabolites levels due to this kind of response. These metabolites will lead the recruitment of transcriptional regulatory complexes to DNA, thus clearly influencing the dynamic chromatin landscape.KEYWORDS: metabolites, enzymes, epigenetics, chromatin, nutrition

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The Role of Aberrant DNA Methylation in Misregulation of Gene Expression in Gonadotroph Nonfunctioning Pituitary Tumors

Cancers ◽

10.3390/cancers11111650 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1650 ◽

Cited By ~ 3

Author(s):

Paulina Kober ◽

Joanna Boresowicz ◽

Natalia Rusetska ◽

Maria Maksymowicz ◽

Agnieszka Paziewska ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Pituitary Tumors ◽

Aberrant Methylation ◽

Qrt Pcr ◽

Open Sea ◽

Aberrant Dna Methylation ◽

Positive Correlations ◽

Affect Gene Expression

Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in 32 NFPAs and normal pituitary sections using methylation arrays and sequencing, respectively. Ten percent of differentially methylated CpGs were correlated with gene expression, and the affected genes are involved in a variety of tumorigenesis-related pathways. Different proportions of gene body and promoter region localization were observed in CpGs with negative and positive correlations between methylation and gene expression, and different proportions of CpGs were located in ‘open sea’ and ‘shelf/shore’ regions. The expression of ~8% of genes differentially expressed in NFPAs was related to aberrant methylation. Methylation levels of seven CpGs located in the regulatory regions of FAM163A, HIF3A and PRSS8 were determined by pyrosequencing, and gene expression was measured by qRT-PCR and immunohistochemistry in 83 independent NFPAs. The results clearly confirmed the negative correlation between methylation and gene expression for these genes. By identifying which aberrantly methylated CpGs affect gene expression in gonadotrophinomas, our data confirm the role of aberrant methylation in pathogenesis of gonadotroph NFPAs.

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MicroRNAs, epigenetics and disease

Essays in Biochemistry ◽

10.1042/bse0480165 ◽

2010 ◽

Vol 48 ◽

pp. 165-185 ◽

Cited By ~ 24

Author(s):

Asli Silahtaroglu ◽

Jan Stenvang

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Target Genes ◽

Regulation Of Gene Expression ◽

Specific Gene ◽

Rna Molecules ◽

Normal Differentiation ◽

Affect Gene Expression ◽

Epigenetic Processes

Epigenetics is defined as the heritable chances that affect gene expression without changing the DNA sequence. Epigenetic regulation of gene expression can be through different mechanisms such as DNA methylation, histone modifications and nucleosome positioning. MicroRNAs are short RNA molecules which do not code for a protein but have a role in post-transcriptional silencing of multiple target genes by binding to their 3′ UTRs (untranslated regions). Both epigenetic mechanisms, such as DNA methylation and histone modifications, and the microRNAs are crucial for normal differentiation, development and maintenance of tissue-specific gene expression. These mechanisms also explain how cells with the same DNA content can differentiate into cells with different functions. Changes in epigenetic processes can lead to changes in gene function, cancer formation and progression, as well as other diseases. In the present chapter we will mainly focus on microRNAs and methylation and their implications in human disease, mainly in cancer.

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Plant simple sequence repeats: distribution, variation, and effects on gene expression

Genome ◽

10.1139/g07-110 ◽

2008 ◽

Vol 51 (2) ◽

pp. 79-90 ◽

Cited By ~ 12

Author(s):

Natalya Sharopova

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Simple Sequence Repeat ◽

Expression Data ◽

Sequence Repeat ◽

Level Control ◽

Functional Annotations ◽

Genome Wide ◽

Affect Gene Expression ◽

Simple Sequence

Genome-wide simple sequence repeat (SSR) information was analyzed together with functional annotations of Arabidopsis genes and public gene expression data for Arabidopsis and rice. Analysis of more than 15 000 Arabidopsis and more than 16 000 rice SSRs indicated that SSRs may affect the expression of hundreds of genes. Data from experiments on DNA methylation, histone acetylation, and transcript turnover suggest that SSRs may affect gene expression at transcriptional and posttranscriptional levels. Members of some functional groups were shown to be enriched with SSRs and often contained similar but non-homologous repeats within the same gene regions. In addition, the distribution of perfect and imperfect SSRs in some Arabidopsis, maize, and rice genes was used to demonstrate how two-level control of SSR variation may contribute to protein evolution.

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The enhancer activity of long interspersed nuclear element derived microRNA 625 induced by NF-κB

Scientific Reports ◽

10.1038/s41598-021-82735-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hee-Eun Lee ◽

Sang-Je Park ◽

Jae-Won Huh ◽

Hiroo Imai ◽

Heui-Soo Kim

Keyword(s):

Gene Expression ◽

Transposable Elements ◽

Human Genome ◽

Dna Sequences ◽

Binding Sites ◽

Luciferase Assay ◽

Enhancer Activity ◽

Long Interspersed Nuclear Elements ◽

Long Interspersed Nuclear Element ◽

Affect Gene Expression

AbstractTransposable elements (TEs) are DNA sequences that cut or introduced into the genome, and they represent a massive portion of the human genome. TEs generate a considerable number of microRNAs (miRNAs) are derived from TEs (MDTEs). Numerous miRNAs are related to cancer, and hsa-miRNA-625 is a well-known oncomiR derived from long interspersed nuclear elements (LINEs). The relative expression of hsa-miRNA-625-5p differs in humans, chimpanzees, crab-eating monkeys, and mice, and four primers were designed against the 3′UTR of GATAD2B to analyze the different quantities of canonical binding sites and the location of miRNA binding sites. Luciferase assay was performed to score for the interaction between hsa-miRNA-625 and the 3′UTR of GATAD2B, while blocking NF-κB. In summary, the different numbers of canonical binding sites and the locations of miRNA binding sites affect gene expression, and NF-κB induces the enhancer activity of hsa-miRNA-625-5p by sharing the binding sites.

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Epigenetic Mechanisms Mediate Nicotine-Induced Reward and Behaviour in Zebrafish

Current Neuropharmacology ◽

10.2174/1570159x19666210716112351 ◽

2021 ◽

Vol 19 ◽

Author(s):

Maria Paula Faillace ◽

Ramón O. Bernabeu

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Epigenetic Regulation ◽

Histone Deacetylases ◽

Dna Methyltransferase ◽

Dopamine Neurons ◽

Epigenetic Mechanisms ◽

Chemical Modifications ◽

Simultaneous Treatment ◽

Polymerase Binding

: Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in installing persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2’-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific impact on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate gene expression epigenetic regulation should be considered a potential therapeutic method to treat nicotine addiction.

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Twenty-four–nucleotide siRNAs produce heritable trans-chromosomal methylation in F1 Arabidopsis hybrids

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613623113 ◽

2016 ◽

Vol 113 (44) ◽

pp. E6895-E6902 ◽

Cited By ~ 15

Author(s):

Ian K. Greaves ◽

Steven R. Eichten ◽

Michael Groszmann ◽

Aihua Wang ◽

Hua Ying ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Epigenetic Reprogramming ◽

The Other ◽

F1 Hybrid ◽

Methylation State ◽

Independent Mechanism ◽

Affect Gene Expression

Hybrid Arabidopsis plants undergo epigenetic reprogramming producing decreased levels of 24-nt siRNAs and altered patterns of DNA methylation that can affect gene expression. Driving the changes in methylation are the processes trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM). In TCM/TCdM the methylation state of one allele is altered to resemble the other allele. We show that Pol IV-dependent sRNAs are required to establish TCM events. The changes in DNA methylation and the associated changes in sRNA levels in the F1 hybrid can be maintained in subsequent generations and affect hundreds of regions in the F2 epigenome. The inheritance of these altered epigenetic states varies in F2 individuals, resulting in individuals with genetically identical loci displaying different epigenetic states and gene expression profiles. The change in methylation at these regions is associated with the presence of sRNAs. Loci without any sRNA activity can have altered methylation states, suggesting that a sRNA-independent mechanism may also contribute to the altered methylation state of the F1 and F2 generations.

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Long antisense non-coding RNAs and the epigenetic regulation of gene expression

BioMolecular Concepts ◽

10.1515/bmc-2013-0014 ◽

2013 ◽

Vol 4 (4) ◽

pp. 411-415 ◽

Cited By ~ 28

Author(s):

Nadia Vadaie ◽

Kevin V. Morris

Keyword(s):

Gene Expression ◽

Human Genome ◽

Protein Complexes ◽

Regulation Of Gene Expression ◽

Biological Significance ◽

Genome Project ◽

Positive Role ◽

Protein Coding ◽

Encode Project ◽

Non Coding Rnas

AbstractShortly after the completion of the human genome project in 2003, the Encode project was launched. The project was set out to identify the functional elements in the human genome, and unexpectedly it was found that >80% of the genome is transcribed. The Encode project identified those transcribed regions of the genome to be encoded by non-coding RNAs (ncRNAs). With only 2% of the genome carrying gene-encoding proteins, the conundrum was then, what is the function, if any, of these non-coding regions of the genome? These ncRNAs included both short and long RNAs. The focus of this review will be on antisense long non-coding RNAs (lncRNAs), as these transcripts have been observed to play a role in gene expression of protein-coding genes. Some lncRNAs have been found to regulate protein-coding gene transcription at the epigenetic level, whereby they suppress transcription through the recruitment of protein complexes to target loci in the genome. Conversely, there are lncRNAs that have a positive role in gene expression with less known about mechanism, and some lncRNAs have been shown to be involved in post-transcriptional processes. Additionally, lncRNAs have been observed to regulate their own expression in a positive feedback loop by functioning as a decoy. The biological significance of lncRNAs is only just now becoming evident, with many lncRNAs found to play a significant role in several human diseases.

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DNA methylation in satellite repeats disorders

Essays in Biochemistry ◽

10.1042/ebc20190028 ◽

2019 ◽

Vol 63 (6) ◽

pp. 757-771 ◽

Cited By ~ 4

Author(s):

Claire Francastel ◽

Frédérique Magdinier

Keyword(s):

Dna Methylation ◽

Human Genome ◽

Repetitive Dna ◽

Dna Sequences ◽

Satellite Repeats ◽

Tremendous Progress ◽

Genes Encoding ◽

Dna Elements ◽

Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

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