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epigenetics

Thursday 20 November 2003

Definition: Epigenetics refers to the stable and heritable changes in gene expression that are not directly attributable to DNA sequence alterations. These changes may affect expression of a gene or the properties of its product. Important epigenetic mechanisms include DNA methylation, changes in chromatin configuration, imprinting, changes in protein confirmation, and RNA-associated silencing. These epigenetic mechanisms provide an “extra” layer of transcriptional control that regulates gene expression.

Epignetic mechanisms

Mechanisms include chromatin remodeling through histone modification and DNA methylation, RNA associated gene silencing and chromosome inactivation, and genomic imprinting.

These epigenetic mechanisms provide an added layer of transcriptional control of gene expression beyond those associated with variation in the sequence of the DNA. Variation in epigenetic regulation helps explain genetic diversity, but significant changes in epigenetic regulation can produce diseases.

Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes.

Functions

Genome-wide epigenetic modification plays a pivotal role in regulating gene expression through chromatin structure and stability, tissue-specific and embryonic developmental specific gene regulation, and genomic imprinting.

Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue- and cell-type-specific functions.

With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes.

Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability.

Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state.

In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli.

Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.

Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators.

Cancer epigenetics

Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance.

In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.

Epigenetic biomarkers - Epigenetic Diagnostics

Epigenetic marks, such as DNA methylation and histone modifications, comprise part of the epigenetic machinery leading to abnormal gene expression and chromatin instability in disease. Epigenetic changes, particularly in human cancers, are now being considered as novel biological markers for diagnostic and therapeutic utility.

The epigenetic drugs

Epigenetics is central to our understanding of the dynamic and adaptive nature of cancer cell phenotypes that cannot be explained by the constraints of genetic alterations.

DNA methylation and histone modifications are the best characterized of the different layers of epigenetic dysregulation of human tumors.

Both sets of epigenetic marks may also affect DNA sequences that give rise to
microRNAs. The first epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, are used for the treatment of leukemias and lymphomas.

A new generation of epigenetic drugs targeting histone methyltransferases, histone demethylases, sirtuins, and the microRNA machinery is rapidly emerging.

See also

- epigenetics of cancer (cancer epigenetics)
- epigenetic therapy of cancer
- epigenetic drugs

Links

- The Human Epigenome Consortium

Free references

- Lund AH, van Lohuizen M. Epigenetics and cancer. Genes Dev. 2004 Oct 1;18(19):2315-35. PMID: #15466484#

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