DNA methylation

DNA methylation is a biochemical process that involves the addition of a methyl group (-CH3) to the DNA molecule.

Two nucleobases have been found on which natural, enzymatic DNA methylation takes place: adenine and cytosine. 

Two of DNA’s four bases, cytosine and adenine, can be methylated. 

This process mainly occurs at specific regions of the DNA called CpG sites, where a cytosine nucleotide is followed by a guanine nucleotide.

The addition of methyl groups to DNA can have significant effects on gene expression and function.

DNA methylation plays a crucial role in the regulation of gene expression.

Methylation can change the activity of a DNA segment without changing the sequence. 

The presence of methyl groups on CpG sites inhibits gene transcription, making it less likely for the gene to be expressed.

By modifying DNA methylation patterns, cells can control which genes are active or silenced.

DNA methylation patterns undergo changes during development and cellular differentiation.

DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.

Such methylation patterns are established early in development and influence cell fate by determining which genes are turned on or off in different cell types.

DNA methylation can be inherited across generations, serving as a form of epigenetic memory.

Some DNA methylation patterns can be passed from parents to offspring and contribute to phenotypic variation and disease risk.

DNA methylation is an epigenetic modification that affects gene expression without altering the DNA sequence itself. 

Methylation can silence gene expression by inhibiting the binding of transcription factors and histone-modifying enzymes to specific DNA sequences.

Methylation of DNA occurs when a methyl group (CH3) is added to the carbon 5 position of a cytosine base in DNA. 

This process is catalyzed by enzymes called DNA methyltransferases.

DNA methylation can occur in both coding and non-coding regions of the genome. 

It is most commonly observed in regions with the CpG sequence (C-phosphate-G), which are repeated in the genome. 

These regions, known as CpG islands, are often found in gene regulatory regions, such as promoters, and have a role in regulating gene expression.

CpG islands are areas of the DNA molecule where the nucleotides cytosine and guanine are frequently found next to each other.

 “CpG” refers to the fact that these two nucleotides are linked together by a phosphate group, forming a specific chemical bond. 

CpG islands are often found near the start sites of genes within the genome, and they play an important role in gene regulation. 

Specifically, DNA methylation which is a process by which a methyl group is added to the DNA molecule of CpG islands can lead to inactivation of nearby genes. 

Abnormal DNA methylation patterns have been associated with various diseases, including cancer, neurodevelopmental disorders, and autoimmune diseases.

The abnormal hypermethylation of tumor suppressor genes in cancer can lead to their silencing and contribute to tumor formation.

DNA (Deoxyribonucleic acid) methylation is a regulator of gene transcription and plays a role in causing hematologic malignancies.

DNA methylation age of blood predicts all-cause mortality in later life.

In proximity of a gene promoter results in stable transcriptional silencing of its expression.

Hypermethylation associated with progression of malignancies, causes arrest in cellular differentiation and is seen in acute leukemia and myelodysplastic syndromes.

DNA methylation occurs across the genome most often at the approximate 28 million CpG sites in the human genome.

Methylation can prevent the transcription machinery from accessing these regions of the DNA molecule and starting the process of gene expression.

CpG islands are associated with a range of biological processes and diseases, including cancer, aging, and neurological disorders.

The pattern of DNA methylation is heritable and can be passed down from one generation to the next. 

Changes in DNA methylation patterns are associated with various diseases, including cancer, as well as developmental disorders.

The process of DNA methylation is dynamic and can be influenced by environmental factors such as diet, lifestyle, and exposure to toxins. 

CpG islands are usually defined as regions with: 1) a length greater than 200bp, 2) a G+C content greater than 50%, 3) a ratio of observed to expected CpG greater than 0.6, although other definitions are sometimes used.

There are around 25,000 CpG islands in the human genome, 75% of which being less than 850bp long.

CpG islands are major regulatory units and around 50% of CpG islands are located in gene promoter regions, while another 25% lie in gene bodies, often serving as alternative promoters. 

Reciprocally, around 60-70% of human genes have a CpG island in their promoter region.

The majority of CpG islands are constitutively unmethylated.

DNA methylation may affect the transcription of genes in two ways: First, methylation of DNA itself may physically impede the binding of transcriptional proteins to the gene.

Second, methylated DNA may be bound by proteins known as methyl-CpG-binding domain proteins (MBDs), which recruit additional proteins to the locus, modifying histones and forming compact, inactive chromatin, termed heterochromatin. 

DNA methylation and chromatin structure linkage is important, as loss of methyl-CpG-binding protein 2 has been implicated in Rett syndrome; and methyl-CpG-binding domain protein 2 mediates the transcriptional silencing of hypermethylated genes in malignancy.

DNA methylation is a powerful transcriptional repressor, at least in CpG contexts. 

DNA methylation is enriched in the body of highly transcribed genes.

Gene body methylation could regulate splicing and suppress the activity of intragenic transcriptional units.

In many disease processes, such as cancer, gene promoter CpG islands acquire abnormal hypermethylation, which results in transcriptional silencing that can be inherited by daughter cells following cell division.

Alterations of DNA methylation are an important component of cancer development. 

Hypomethylation is linked to chromosomal instability.

 Hypermethylation is associated with promoters and can arise secondary to oncogene suppressor silencing.

Hypomethylation has also been implicated in the development and progression of cancer through different mechanisms.

There is hypermethylation of tumor suppressor genes and hypomethylation of oncogenes.

In the progression to cancer, hundreds of genes are silenced or activated. 

The  silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation.

DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.

Altered expressions of microRNAs also silence or activate many genes in progression to cancer.

Silencing of DNA repair genes through methylation of CpG islands in their promoters is important in the progression to cancer.

Epigenetic modifications with DNA methylation is implicated in cardiovascular disease, including atherosclerosis. 

DNA methylation polymorphisms may be used as an early biomarker of atherosclerosis, being present before lesions are observed.

Cell types targeted for DNA methylation polymorphisms are monocytes and lymphocytes, which experience an overall hypomethylation. 

High plasma levels of homocysteine inhibit DNA methyltransferases, which causes hypomethylation with increasing risk of cardiovascular disease.

Hypomethylation of DNA affects genes that alter smooth muscle cell proliferation, cause endothelial cell dysfunction, and increase inflammatory mediators, all of which are critical in forming atherosclerotic lesions.

High levels of homocysteine result in hypermethylation of CpG islands in the promoter region of the estrogen receptor alpha (ERα) gene, causing its down regulation.

ERα protects against atherosclerosis due to its action as a growth suppressor, causing the smooth muscle cells to remain in a quiescent state.

Hypermethylation of the ERα promoter thus allows intimal smooth muscle cells to proliferate excessively and contribute to the development of the atherosclerotic lesion.

In ischemic heart failure DNA methylation changes have been linked to changes in gene expression that may direct gene expression associated with the changes in heart metabolism.

DNA methylation levels can be used to estimate the age of tissues and cell types, allowing an assessment of the epigenetic clock.

Twin studies of children showed that, between the ages of 5 and 10, there is divergence of methylation patterns due to environmental rather than genetic influences.

There is a loss of DNA methylation during aging, and that the loss is proportional to age

Hypomethylated CpGs is observed in the centenarian DNAs compared with the neonates in all genomic compartments; promoters, intergenic, intronic and exonic regions/

However, some genes become hypermethylated with age, including genes for the estrogen receptor, p16, and insulin-like growth factor 2.

High intensity exercise reduces DNA methylation in skeletal muscle.

DNA methylation alterations in brain neurons are important in learning and memory.

Mass spectrometry is a sensitive, reliable method to detect DNA methylation. 

DNA methylation is associated with cell differentiation and proliferation.

DNA methylation allows for several tissues to be analyzed in one assay as well as for small amounts of body fluid to be identified with the use of extracted DNA. 

DNA methylation provides a relatively good means of sensitivity when identifying and detecting body fluids. 

The detection of DNA methylation in cell-free DNA and other body fluids is one of the main approaches to Liquid biopsy.

In particular, the identification of tissue-specific and disease-specific patterns allows for non-invasive detection and monitoring of diseases such as cancer.

The frequency of methylation changes with age, both increasing at some sites and decreasing at others.

Methylation clocks can help predict chronological age, and age related biological changes, or to predict mortality.

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