What is the Effect of DNA Methylation on Gene Expression

Epigenetics is the study of heritable changes in the expression of genes or heritable changes in the phenotype of a particular organism that do not occur due to the changes in the nucleotide sequence of a gene. The epigenetic regulation of gene expression plays a critical role in cell functioning as it is involved in the tissue-specific gene expression, inactivation of X chromosome, and genomic imprinting (the expression of genes in a parent-of-origin-specific manner). Furthermore, disorders in the expression of genes that are regulated epigenetically cause diseases including cancers. The mechanisms involved in the epigenetic gene regulation are DNA methylation, untranslated RNAs, chromatin structure, and modification. This article describes the effect of DNA methylation on gene expression.

Key Areas Covered

1. What is DNA Methylation
     – Definition, Distribution in the Genome, Importance
2. What is the Effect of DNA Methylation on Gene Expression
     – Function of Methylation
3. What is the Role of DNA Methylation in Cell Functioning
     – Tissue-Specific Gene Expression, Inactivation of X chromosome, Genomic Imprinting

Key Terms: CpG Islands, DNA Methylation, Epigenetics, Genomic Imprinting, Tissue-Specific Gene Expression, X-Inactivation

What is DNA Methylation

DNA methylation refers to the addition of a methyl group (-CH₃) to the nitrogenous base cytosine (C) covalently at the 5′-CpG-3′ sites. A CpG site is a region of DNA where cytosine nucleotide is followed by a guanine nucleotide along the 5′ to 3′ direction of a linear DNA strand. The cytosine is linked to the guanine nucleotide through a phosphate (p) group. DNA methylation is regulated by DNA methyltransferase. The unmethylated and methylated cytosine is shown in figure 1.

Figure 1: Unmethylated and Methylated Cytosine

The unmethylated CpG sites can be either randomly distributed or arranged in clusters. The clusters of CpG sites are called ‘CpG islands’. These CpG islands occur in the promoter region of many genes. The housekeeping genes, which are expressed in most of the cells, contain unmethylated CpG islands. In many cases, the methylated CpG islands cause the repression of genes. Hence, DNA methylation controls the expression of genes in different tissues as well as at specific times in life such as at embryonic development. Throughout the evolution, DNA methylation is important as a defense mechanism in the host cell in silencing replicated transposable elements, repetitive sequences, and foreign DNA such as viral DNA.

What is the Effect of DNA Methylation on Gene Expression

The epigenetic marking of the CpG sites of the genomes is unique to species. It is stable throughout the lifetime as well as heritable. Many CpG sites are methylated in the human genome. The main function of DNA methylation is to regulate the gene expression depending on the requirements of a particular cell. Typical DNA methylation landscape in mammals is shown in figure 2.

Figure 2: DNA Methylation Landscape in Mammals

The gene expression is initiated by the binding of transcription factors to the regulatory sequences of genes such as enhancers. The changes brought to the chromatin structure by DNA methylation restrict the access of transcription factors to the regulatory sequences. In addition, methylated CpG sites attract methyl-CpG-binding domain proteins, recruiting the repressor complexes responsible for the histone modification. Histones are the protein component of chromatin that alter the wrapping of DNA. This forms more condensed chromatin structures known as heterochromatin, inhibiting the gene expression. On the contrary, euchromatin is a type of loosen chromatin structures that allows the gene expression.

What is the Role of DNA Methylation in Cell Functioning

Generally, DNA methylation patterns in a particular cell are very stable and specific. It is involved in the tissue-specific gene expression, inactivation of X chromosome, and genomic imprinting.

Tissue-Specific Gene Expression

The cells of the tissues are differentiated to perform a specific function in the body. Therefore, proteins that serve as structural, functional, and regulatory elements of the cells should be expressed in a differential manner. This differential expression of proteins is achieved by the differential patterns of DNA methylation of genes in each type of tissues. As genes in the genome in every type of cells in a particular organism are the same, the genes that need not be expressed in a tissue contains methylated CpG islands in their regulatory sequences. However, the patterns of DNA methylation during the embryonic development differ from those in the adult stage. In cancer cells, the regular pattern of DNA methylation differs from a normal cell of that tissue. DNA methylation patterns in normal and cancer cells are shown in figure 3.

Figure 3: DNA Methylation Patterns in Normal and Cancer Cells

Inactivation of X Chromosome

Females have two X chromosomes while males have an X chromosome and Y chromosome in their genome. One of the X chromosome from females should be inactivated during development. This is accomplished by de novo methylation. The inactivation of the X chromosome maintains it in the silent stage by forming heterochromatin. The X-inactivation prevents the expression of gene products related to X chromosome as twice as in males. In placental mammals, the choice of inactivating the X chromosome is random. However, when inactivated, it remains silent throughout the lifetime. However, in marsupials, the paternally-derived X chromosome is inactivated exclusively.

Genomic Imprinting

Genomic imprinting refers to the selective expression of genes depending on the origin of the parental chromosome. As an example, the paternal copy of the insulin-like growth factor 2 (IGF2) gene is active while the maternal copy is inactive. However, the opposite is true for the H19 gene, which is closely located on the IGF2 gene in the same chromosome. About 80 genes of the human genome are imprinted. DNA methylation is responsible for the inactivation of one parental copy of a particular gene.

Conclusion

The regulation of gene expression through epigenetic changes in genes is a stable and heritable characteristic of many genomes. One of the key mechanisms of epigenetic gene regulation is DNA methylation. DNA methylation is the permanent addition of a methyl group to a cytosine residue in a CpG site. Methylated CpG islands near the regulatory sequences of genes repress the transcription of that particular genes. Hence, these genes remain silent. The silence of genes through DNA methylation is important in tissue-specific gene expression, X-inactivation, and genomic imprinting.

Reference:

1. Lim, Derek H K, and Eamonn R Maher. “DNA methylation: a form of epigenetic control of gene expression.” The Obstetrician & Gynaecologist, Blackwell Publishing Ltd, 24 Jan. 2011, Available here.
2. Razin, A, and H Cedar. “DNA methylation and gene expression.” Microbiological reviews., U.S. National Library of Medicine, Sept. 1991, Available here.

Image Courtesy:

1. “DNA methylation” By Mariuswalter – Own work (CC BY-SA 4.0)  via Commons Wikimedia
2. “DNAme landscape” By Mariuswalter – Own work (CC BY-SA 4.0) via Commons Wikimedia
3. “DNA methylation in a normal cell vs. in a cancer cell”By Ssridhar17 – Own work (CC BY-SA 4.0) via Commons Wikimedia