CpG island hypermethylation

Algorithm

CytosineMethylation

DNA methylation in a normal cell vs. in a cancer cell

Epigenetic alterations in tumour progression

CpG Island Hypermethylation is a crucial epigenetic modification that plays a significant role in the regulation of gene expression and has been extensively studied in the context of cancer and other diseases. CpG islands are regions in the DNA that are rich in cytosine and guanine nucleotides, located near the promoters of genes. Hypermethylation of these CpG islands can lead to the silencing of gene expression, which can have profound effects on cellular function and disease development.

Overview

CpG islands are typically 300-3,000 base pairs in length and are found in the promoter regions of approximately 70% of human genes. These regions are normally unmethylated in healthy cells, allowing for the active transcription of genes. However, in certain diseases such as cancer, CpG islands can become hypermethylated. This hypermethylation is a key mechanism of gene silencing, preventing the binding of transcription factors and, consequently, the expression of the gene.

Mechanism

The process of CpG island hypermethylation involves the addition of a methyl group to the 5' position of the cytosine ring within CpG dinucleotides by DNA methyltransferases (DNMTs). This modification can alter the chromatin structure, making it more compact and less accessible to transcription factors and the transcriptional machinery, thus silencing gene expression. The silencing of tumor suppressor genes through hypermethylation is a common feature in the development of cancer, contributing to tumor progression and the evasion of cellular control mechanisms.

Role in Cancer

In cancer, CpG island hypermethylation is frequently observed in tumor suppressor genes, leading to their inactivation. This epigenetic alteration is considered an early event in the carcinogenesis process and has been detected in various types of cancer, including breast cancer, colorectal cancer, and lung cancer. The hypermethylation of CpG islands in these genes can contribute to uncontrolled cell growth, evasion of apoptosis, increased invasion, and metastasis.

Detection and Clinical Implications

The detection of CpG island hypermethylation is of great interest for the development of diagnostic, prognostic, and therapeutic strategies. Techniques such as bisulfite sequencing, methylation-specific PCR (MSP), and pyrosequencing are commonly used to assess the methylation status of CpG islands. Identifying hypermethylated genes in tumors can help in understanding the molecular mechanisms underlying cancer and in identifying potential biomarkers for early detection, prognosis, and response to therapy.

Therapeutic Approaches

The reversible nature of DNA methylation has made it a target for therapeutic intervention. Drugs that inhibit DNMTs, such as azacitidine and decitabine, have been approved for the treatment of certain types of cancer. These demethylating agents can reactivate silenced genes, restoring normal cellular functions and potentially inhibiting tumor growth.

Conclusion

CpG island hypermethylation is a fundamental epigenetic modification with significant implications for gene expression, cellular function, and the development of disease, particularly cancer. Understanding the mechanisms and consequences of CpG island hypermethylation continues to be a major focus of research, with the potential to improve disease diagnosis, prognosis, and treatment.