Epigenetics is the study of changes in gene expression patterns due to mechanisms other than mutations in the underlying DNA sequence. Epigenetic modifications are inherited by daughter cells during cell division. The changes in gene expression associated with epigenetics are governed by alterations in chromatin structure.
In the nucleus, DNA is associated with a class of structural and regulatory proteins called histones. The nucleosome refers to the units of DNA spooled around histone complexes, typically structured as heterotetramers (two copies of four different histone proteins). Stretches of DNA between individual nucleosomes are referred to as linker DNA. The highly ordered packaging of DNA and histones together is called chromatin.
Chromatin structure influences the accessibility of promoter regions to transcription factors. The accessibility, or lack of accessibility, of promoter DNA represents a major means of transcriptional regulation and is at the center of epigenetic gene regulation. Relaxed chromatin, also known as euchromatin, allows transcription factors more ready access to promoter sites, thereby facilitating activation of transcription. In contrast, heterochomatin is densely compacted to varying degrees, often concealing DNA promoter sequences from potential transcription factors. Epigenetic markers (or marks) are the modifications to histone proteins and DNA that modulate the affinity of chromatin-binding proteins, in turn altering chromatin structure.
Researchers are interested in understanding the role of epigenetics in disease progression. The activity of enzymes that modify histones can be affected by environmental factors, such as toxins or stress, leading to alterations in gene transcription. Aberrant methylation has been well correlated with gene silencing and the development of several cancers.
Biomedical research is exploring if epigenetic regulations can be exploited for the development of novel drug therapies. For example, abnormal changes in chromatin conformation associated with the development of cancer might be reversible with the proper therapeutic. Epigenetic therapies, such as manipulating the chromatin conformation of specific genes to activate or repress transcription, would appear to be far more achievable than genetic therapies requiring precise DNA sequence modifications.
Stem cell researchers are actively and aggressively exploring epigenetics. Stem cells are unique in that they have not assumed a particular cell fate and retain the potential to become a variety of tissue types — a cellular state referred to as pluripotency. Studies of the epigenetic changes that occur during stem cell differentiation have provided clues to how the epigenetic status of cells may impact pluripotency. Epigenetic manipulations may enable researchers to more accurately direct differentiation of cells into desired cell types and may aid in the generation of induced pluripotent stem cells, the practice of reprogramming fully differentiated cells back toward a state of pluripotency.
While most genes in autosomal cells are simultaneously expressed from both alleles, a small proportion of genes are expressed in a monoallelic fashion. Imprinting is the process through which one of two alleles for a given gene is silenced in a parent-of-origin specific pattern. Imprinting is considered a form of epigenetics because it leads to heritable changes in gene expression despite a lack of changes in the genomic code.
The silencing of one allele in imprinting is achieved through DNA methylation and histone modifications. Non-protein coding RNAs greater than 200 bp in length (long ncRNAs) play a role in genomic imprinting by recruiting chromatin remodeling complexes to regions of the genome that are silenced.
Genetic imprinting has been linked to the development of several diseases, including various forms of cancer. Various oncogenes and tumor suppressor genes appear to demonstrate patterns of imprinting. Given the potential role for gene imprinting in disease progression, scientists are actively investigating how epigenetic modifications impact monoallelic gene expression.
Researchers are also examining the potential for epigenetic markers to serve as biomarkers for disease. Biomarkers are diagnostic correlates that aid in the prognosis and diagnosis of diseases. Indeed, differences in epigenetic patterns between diseased and healthy tissues are apparent. Current efforts in biomarker research predominantly examine DNA methylation patterns in tissue biopsies (Laird 2010). It is possible that epigenetic changes may aid in disease diagnosis and help dictate the most appropriate therapeutic approaches for treating patients.
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