Epigenetic Modification: Types, Functions, and Applications in Disease and Development

Epigenetic modification represents a sophisticated regulatory mechanism in biology. It involves the modulation of gene expression through chemical alterations or changes in chromatin structure, all while leaving the underlying DNA sequence intact. This mode of regulation has far – reaching implications for a wide range of biological processes, from cellular differentiation during development to the onset and progression of diseases.

What is Epigenetic Modification

Epigenetic modification is a kind of genetic regulation mode that does not change the DNA sequence, and affects the transcription activity of genes by regulating the advanced structure or chemical modification of chromatin. For example, DNA methylation usually leads to gene silencing, while histone acetylation promotes gene transcription. These modifications can be inherited and passed on to future generations, thus playing an important role in cell differentiation and development.

It is reporeted that epigenetic modification is a kind of genetic regulation mode that does not change the DNA sequence, and affects the transcription activity of genes by regulating the advanced structure or chemical modification of chromatin. For example, DNA methylation usually leads to gene silencing, while histone acetylation promotes gene transcription. These modifications can be inherited and passed on to future generations, thus playing an important role in cell differentiation and development.

Summary of epigenetic methodolody

Epigenetic modification has a wide and far-reaching influence on biological processes. They not only participate in the regulation of cell differentiation, tissue development and organ function, but also play an important role in environmental adaptation, disease occurrence and intergenerational transmission.

Development and differentiation: Epigenetic modification ensures the correct choice of cell fate and the formation of tissue specificity by regulating gene expression.

Environmental adaptation: Epigenetic modification enables organisms to quickly respond to environmental changes, for example, by adjusting gene expression to adapt to temperature, nutrition or other external pressures.

Disease occurrence: Abnormal epigenetic modification is closely related to the occurrence of many diseases, including cancer, neurodegenerative diseases and metabolic diseases.

Cross-generational transmission: Epigenetic modification can be transmitted to offspring through germ cells, thus achieving cross-generational adaptation.

Epigenetic modifications occur on different biological scales (Lombardo et al., 2022)

Main Types of Epigenetic Modification

The main types of epigenetic modification are DNA methylation, which means adding methyl groups to specific DNA regions through DNA methyltransferase to regulate gene expression. Histone modification, including histone methylation, acetylation and phosphorylation, can change the structure and function of chromatin and then affect gene expression. Non-coding RNA regulation, such as microRNA (miRNA) inhibits translation or promotes its degradation by binding to target mRNA, long-chain non-coding RNA (lncRNA) plays a regulatory role at transcription and post-transcription level, and circular RNA (circRNA) indirectly regulates gene expression mainly by adsorbing mirna.

DNA methylation: DNA methylation is one of the most prevalent epigenetic modifications. It occurs when DNA methyltransferases add methyl groups to the 5th carbon of cytosine residues, resulting in the formation of 5 – methyl cytosine. This modification frequently takes place in the promoter region of genes. In cancer, an imbalance in DNA methylation is a well – documented phenomenon. Aberrant hypermethylation of tumor – suppressor genes can lead to their silencing, preventing them from performing their normal function of inhibiting cell growth and division. Conversely, hypomethylation of oncogenes can cause their overexpression, promoting uncontrolled cell proliferation.

Summary of studies on epigenetic modifications in the cardiovascular diseases (Wang et al., 2024)

Histone modification: It encompasses a diverse set of chemical alterations, including acetylation, methylation, phosphorylation, and ubiquitination. These modifications predominantly occur in the N – terminal tail region of histones.

• Acetylation: Histone acetylation, which commonly occurs on lysine residues of histones H3 and H4, has a chromatin-loosening effect. By neutralizing the positive charge of lysine residues, acetylation reduces the electrostatic interaction between histones and DNA, making the chromatin more relaxed. This relaxed state promotes gene expression as transcription factors can more easily access the DNA.
• Methylation: The methylation of different histone residues has distinct effects on gene expression. For example, the methylation of histone H3 at lysine 4 (H3K4) is generally associated with gene activation, while methylation at H3K9 and H3K27 is often linked to gene repression.
• Phosphorylation: Histone phosphorylation usually occurs on serine residues of histone H3. It is involved in regulating the cell cycle and also plays a role in gene expression. Phosphorylation can either enhance or inhibit gene expression depending on the specific context and the location of the phosphorylation site.

Non-coding RNA modification: Such as miRNA and lncRNA plays an important role in epigenetic regulation. They can regulate gene expression by binding to mRNA or DNA. For example, the abnormal expression of miR-338-3p in gastric cancer is closely related to epigenetic histone modification.

Chromatin remodeling: It refers to the process of regulating gene expression by changing the three-dimensional structure of chromatin. This usually involves the role of ATP-dependent chromatin remodeling complexes.

Epigenetic gene silencing mechanisms in mammals (Sharma et al., 2010)

Exosomes-mediated: Exosomes are small vesicles released by cells, which carry epigenetic factors such as DNA methylation, histone modification and non-coding RNA. These factors can affect the gene expression of recipient cells through cell-to-cell transfer.

To study these modifications in depth, precise genomic data is required. At CD Genomics, we offer a range of sequencing services that can support your research into epigenetic changes. Our whole genome bisulfite sequencing (WGBS) can help identify and analyze DNA methylation patterns across the genome, providing insights into epigenetic alterations associated with diseases. For a more focused approach, our RNA Sequencing (RNA-Seq) can reveal changes in gene expression driven by histone modifications or non-coding RNAs. Additionally, our ChIP-Seq services allow you to explore histone modifications in detail, offering insights into chromatin remodeling and gene regulation.

If you would like to learn more details, you can check out the following articles:

• Exploring Chromatin Remodeling: New Progress in Gene Regulation, Disease Correlation and Detection Technology
• Choosing the Appropriate DNA Methylation Sequencing Technology
• Epitranscriptomics: An Exploration of RNA Modification, Disease Mechanism and Sequencing Methods
• Histone Modification and Epigenetics: Deciphering the Biological Significance of Histone Modification

Applications of Epigenetic Modification

In the process of DNA demethylation, an enzyme called TET2, which plays a role in the differentiation of hematopoietic stem cells, can cause blood system diseases when mutated. AKG as a histone demethylase can affect the epigenetic state of tumor cells. Its influence on diseases such as cancer is manifested in abnormal DNA methylation (hypomethylation of protooncogene and hypermethylation of tumor suppressor gene), histone modification (such as abnormal high expression of H3K27me3) and non-coding RNA disorder (such as high expression of miR-21 to inhibit tumor suppressor gene). In the treatment of diseases, epigenetics has the potential to develop epigenetic drugs, improve the curative effect by adopting combined treatment strategies, and serve as a marker for disease diagnosis and prognosis (detecting gene methylation level and specific miRNA expression level).

Modification of TET2 and AKG in diseases

TET2 is a DNA methylase, which can transfer methyl groups on DNA to small cofactors, thus regulating gene expression. This modification is usually related to the activation of genes. AKG is a gene that is activated under certain conditions, and its expression is regulated by epigenetic modification. These modifications play an important role in cell differentiation and development, and may also be related to the pathogenesis of some diseases.

Histone modification in diseases

Histone modification includes acetylation, methylation, phosphorylation, etc. These modifications can change chromatin structure, thus affecting gene expression. For example, histone acetylation is usually related to gene activation, while methylation may be related to gene silencing. These modifications play an important role in complex diseases such as cancer and neurodegenerative diseases.

Effect of epigenetic modification on diseases

• Cancer: Epigenetic modification plays a key role in the occurrence and development of cancer. Abnormal DNA methylation may lead to the silence of tumor suppressor genes or the activation of oncogenes, while abnormal histone modification may affect chromatin structure, thus promoting the occurrence and progress of tumors. For example, DNA methylation inhibitors and histone deacetylase inhibitors have been used in cancer treatment, and have shown certain efficacy.

Epigenetic modifications results in transcriptional activation or repression (Bojang et al., 2013)

• Neurodegenerative diseases: Epigenetic modification also plays an important role in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. For example, in the brains of patients with Alzheimer’s disease, the histone modifications of H3K27ac and H3K9ac increase, which affects neurodegeneration. In addition, RNA methylation modification also showed differentiated changes in these diseases.
• Cardiovascular disease: Epigenetic modification also plays an important role in cardiovascular diseases. For example, abnormal DNA methylation and histone modification may affect the function of vascular smooth muscle cells, which may lead to diseases such as atherosclerosis.

Illustration of several underlying epigenetic mechanisms in pulmonary hypertension (Bisserier et al., 2020)

• Immune system diseases: Epigenetic modification also plays an important role in immune system diseases. For example, TET2 and HDAC inhibitors have been used to treat diseases such as rheumatoid arthritis and endometriosis.

Potential of epigenetics in disease treatment

• Cancer treatment: Epigenetics provides a new target for cancer treatment. For example, DNA methylation inhibitors and histone deacetylase inhibitors have been used to treat hematological malignancies, and have shown good curative effects. In addition, epigenetic therapy can restore the normal function of tumor cells by re-expressing silencing genes.
• Personalized medicine: Epigenetic detection technology can be used as a tool for diagnosis and prognosis, helping doctors to make personalized treatment plans. For example, by analyzing the epigenetic markers of patients, the reactivity of chemotherapy drugs or the prognosis of tumors can be predicted.

The essential role of epigenetic changes in regulatory T cell (Treg) development (Szukiewicz et al., 2022)

• Non-cancer disease management: Epigenetic therapy also shows potential in cardiovascular diseases, nervous system diseases and metabolic diseases. For example, the pathophysiological process of cardiovascular diseases can be improved by regulating epigenetic modification.
• Future research direction: Although epigenetics has great potential in the treatment of diseases, further research is needed to overcome the limitations of existing therapies. For example, how to target specific epigenetic modifications more accurately and how to reduce nonspecific effects are still the focus of future research.

Relationship Between Epigenetic Modification and Gene Regulation

There are mainly the following ways to regulate gene opening and closing through epigenetic modification: in DNA methylation, methylation of CpG island in promoter region will hinder transcription factor binding and thus close the gene, while demethylation is beneficial to gene opening. In histone modification, different sites of histone methylation can activate or silence genes, acetylation makes chromatin loose to open gene expression, while deacetylation is the opposite, and phosphorylation can change chromatin structure and function to affect gene expression. In the aspect of non-coding RNA regulation, miRNA can bind with mRNA to inhibit translation or promote its degradation to turn off genes, and may also promote expression. lncRNA can turn on or off genes through various mechanisms at the transcription and post-transcription level, while circRNA indirectly turns on gene expression mainly by adsorbing miRNA to release the inhibition on target mRNA.

The role of epigenetics in cell development

Epigenetics plays a key role in determining the fate of cells, especially in the process of stem cell differentiation and pluripotency maintenance:

• Stem cell differentiation: Epigenetic modification determines the fate of cells by regulating the expression of specific genes. For example, during the differentiation of hematopoietic stem cells, specific histone modification and DNA methylation patterns are reprogrammed to activate genes related to differentiation.

Epigenetic mechanisms implicated in the self-renewal, differentiation, and proliferation of amniotic fluid stem cells (Tizio et al., 2018)

• Regulatory network of cell fate: Epigenetic modification forms a complex regulatory network to control the determination of cell fate. For example, DNA methylation and histone modification work together to regulate chromatin openness and gene expression during stem cell differentiation.
• Influence of environmental factors: Environmental factors (such as diet, toxins, etc.) can affect the fate of cells by changing epigenetic modification. For example, some environmental toxins may cause abnormal DNA methylation, thus affecting cell differentiation.

Relationship between epigenetic modification and genome stability

Epigenetic modification also plays an important role in maintaining genome stability:

• Protecting genome integrity: Epigenetic mechanism protects genome from damage by regulating chromatin structure and DNA repair. For example, DNA methylation and histone modification can enhance the function of spindle and telomere, thus maintaining genome stability.
• Prevention of transposon invasion: Epigenetic modification prevents the active replication of transposons by forming an inhibitory chromatin environment, thus protecting the stability of the genome.
• Coping with environmental stress: Epigenetic modification can respond to environmental factors and adapt to external changes by dynamically adjusting gene expression.

Conclusion

Epigenetic modification is a complex and essential biological process that encompasses DNA methylation, histone modification, and non-coding RNA regulation. These modifications play a crucial role in normal cellular functions, including cell differentiation and development. Aberrant epigenetic modifications are closely associated with the development of various diseases, making them attractive targets for therapeutic intervention. The applications of epigenetic research in disease diagnosis, treatment, and drug development hold great promise for improving human health. However, further research is needed to fully understand the intricate mechanisms of epigenetic regulation and to overcome the challenges associated with epigenetic therapies.

References

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