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Epigenetics and the Etiology of Human Disease


Epigenetics and the Etiology of Human Disease


What Is Epigenetics?

Epigenetics is considered a relatively new branch of genetic research. However, the concept dates back to the 1940s. Then, epigenetics was understood as a mechanism involving gene and gene-product interactions responsible for phenotypic expression. 

Epigenetics is now understood as stable, heritable changes in gene expression not associated with changes in the actual DNA sequence. DNA is not freely floating around in the nucleus of eukaryotic cells. Rather, it is wrapped around an octamer of histone proteins. This complex of DNA and histone octamers is called chromatin.

How tightly the DNA is wrapped around the histone octamer is what determines whether transcription factors can access genes to transcribe the corresponding RNA. Epigenetics is the study of modifications that can alter the degree of wrapping around the histones. This changes gene expression and the phenotype without altering the actual genotype. 

Histone and DNA depiction

Artistic depiction of DNA (yellow and orange) wrapped around a histone (blue). 

Epigenetic regulation occurs in many ways. One of the most extensively studied epigenetic mechanisms is DNA methylation. The presence of a methyl group on the DNA base, cytosine, signals compaction of DNA around histones.

Highly compacted chromatin (DNA + histones) is associated with a lack of gene expression. Alterations in the patterns of DNA methylation are associated with the development of disease states or developmental defects. Changes in gene expression patterns can occur via demethylation and hypermethylation. 

Another group of epigenetic mechanisms includes histone modifications and microRNA regulation. The tails of the histones around which DNA is bound can incur post-translational modifications (PTMs) that contribute to the degree of DNA compaction.

In this article, we explore key moments when epigenomic technologies can help to understand, diagnose, and treat medical conditions. Both microRNAs and other small RNAs are known to signal changes in epigenetic states in a sequence-specific manner. 

Epigenetic Research & Abnormal Embryonic Development

Normal embryonic development is dependent upon properly functioning epigenetic mechanisms. Temporal and structural alterations in DNA methylation patterns lead to a number of developmental defects in animals and humans. In temporal alterations, a DNA methylation pattern that is appropriate at one stage of development may not be appropriate for another. 

Further, an alteration in a specific anatomical region may not occur in another. And even if it does, it may not lead to an adverse change. For example, North Carolina State University researchers demonstrated that treating pregnant female mice with a global demethylating agent leads to altered gene expression in the offspring.

Specifically, alterations in Hox gene levels led to defects in hind limb development. Although changes in the methylation pattern were global, this particular effect was specific for hindlimbs and only occurred during mid-gestation.

It has only recently been shown that xenobiotic-induced gene expression changes, specifically those that did not change the DNA sequence, could be inherited across multiple generations. Cisneros and Branch demonstrated that toxicant exposure can lead to defects in subsequent generations of mice that were not exposed to the toxicant. Defects detected were associated with epigenetic changes, not mutations in actual DNA sequences. 

Epigenetic inheritance is now widely studied in regard to observations seen throughout generations in humans. Changes to epigenetic regulation are not only heritable but can alter the development of somatic cells. 

Developmental Disorders & Abnormalities

A number of developmental abnormalities in humans are linked to epigenetic alterations. For example, Beckwith-Weidemann Syndrome (BWS) is a developmental outgrowth disorder. It is associated with a predisposition towards tumor development. 

Dysregulation of imprinting has been linked to BWS. Imprinting is the expression of genes based on their origin from one parent. In other words, if an allele inherited from the mother is imprinted (epigenetically marked ), it will not be expressed, but the allele from the father will be. 

In BWS, epigenetic alterations are associated with the dysregulation of specific imprinted genes on chromosome 11p15.5. Beckwith-Weidemann syndrome and other imprinting disorders are associated with early assisted reproductive technologies. Improvements in our understanding of mechanisms in epigenetics have led to improvements in methods surrounding assisted reproduction. 

Congenital heart defects (CHD) have been linked to altered DNA methylation. Researchers from the University of Arkansas for Medical Sciences determined the methylation status of thousands of CpG sites from white blood cell DNA taken from pregnant women (CHD-affected and unaffected pregnancies).

Results of the study indicate that altered maternal DNA methylation may be associated with CHDs. Changes or exposures occurring in the mother affect the fetal outcome. Those that occur in the father may also lead to developmental abnormalities. 

Mouse studies showed that paternal diets deficient in vitamin B9 or folate led to higher incidence of developmental defects in offspring when compared to healthy paternal feeding. In the sperm of male mice fed folate-deficient diets, epigenetic markers were altered in genes associated with cancer, schizophrenia, and other conditions.

Changes in parental epigenetic status may be due to environmental, metabolic, or genetic factors. Alterations in methylation may directly affect the developing embryo or fetus. They could even make the embryo more susceptible to toxic agents. Epigenetic alterations to DNA have profound effects on an individual’s development. 

Epigenetics in Diagnostics

Epigenetic biomarkers are valuable targets for accurate disease diagnoses. We are still developing clinical methods to determine differential DNA methylation in rare diseases. However, several instances indicate that DNA methylation detection methods are a potential tool for non-invasive diagnostics. 

For example, analyzing blood or fecal specimens is a possible non-invasive diagnostic approach for early detection of colorectal cancer (CRC) or ovarian cancer. Italian researchers found that the methylation status of septin 9 and vimentin genes are viable candidates for the non-invasive diagnosis of CRC. Research on ovarian cancer has shown that differences in p16 gene methylation can distinguish between benign and malignant ovarian tumors.

Epigenetic analysis can also facilitate the diagnosis of diseases other than cancer. Facioscapulohumeral muscular dystrophy 1 (FSHD1) can be diagnosed using DNA restriction methods, electrophoresis, and Southern blotting. However, FSHD2 cannot be diagnosed by this means. A 2014 study found that FSHD1 and FSHD2 can be diagnosed and distinguished by investigating the epigenetic signature of genomic DNA isolated from blood or saliva. 

Prenatal Testing & Diagnostics

Prenatal testing for developmental defects using epigenetic markers has a promising future. Using chorionic villus samples from women with healthy pregnancies, Paganini et al. tested the methylation levels of various imprinted loci associated with BWS. This research found that the ICR1 and ICR2 loci could be reliable diagnostic targets for testing methylation status to diagnose BWS. 

Noninvasive prenatal diagnosis of Down syndrome via next-generation sequencing (NGS) using maternal blood is already possible. This technique relies on the detection of trisomy on chromosome 21. Using shotgun sequencing on plasma samples from pregnant women, it was possible to measure over- and underrepresentation of fetal chromosomes. 

Identifying Treatment Targets

The analysis of epigenetic markers also shows promise in identifying potential drug targets in many diseases. For example, epigenetics is an area of active research aimed at developing treatments for Alzheimer’s disease. Epigenetic alterations, including DNA methylation and histone modifications, are related to functions of learning and memory. By identifying reversible treatment targets, researchers are making strides toward effective therapeutics for Alzheimer’s disease.

Multiple epigenetic-based therapies are currently being investigated. Potential targets for these therapies include DNA methylation and histone acetylation inhibitors. 5-aza-2`-deoxycytidine (a DNA demethylating agent), has helped open the door to the study and characterization of DNA methylation's control of gene expression. This drug is used as a treatment for myeloid leukemia and myelodysplastic syndromes.    

Future Human Clinical or Epidemiological Studies

Our understanding of epigenetics provides a valuable perspective on disease treatment and detection. State-of-the-art technologies can help researchers study epigenetic status in biological tissues. Next-generation sequencing and microarray approaches can detect changes in DNA methylation patterns. The combination of bisulfite conversion with NGS has permitted the genome-wide analysis of DNA methylation and new technologies like the PacBio Revio can detect methylation directly, without bisulfite treatment. 

In addition, microarray technology makes it possible to detect DNA methylation differences between tissue types. These technologies have uncovered connections between altered epigenetic mechanisms and disease. Not only has this allowed an increase in the understanding of disease etiology, but it may reveal therapeutic targets to restore normal physiological function.

Modern epigenetic tools have caused a dramatic increase in epidemiological research, changing our understanding of disease. With further studies, we will gain a better perspective on disease development, treatment targets, inheritance, and much more.