A reasonably simple introduction to epigenetics

Alan Horsager, Ph.D.
June 8, 2018

Epigenetics is the study of molecules that sit on top of DNA and control the way your genes work. Certain epigenetic elements can control the activity of DNA, turning some genes on and others off. In some regards, epigenetics is simply the study of gene expression.

For the most part, every cell in the human body contains an identical set of chromosomes that is made up of the same DNA sequence. But different cells in the body (e.g., neurons or skin cells) are functionally different. This is because a different set of genes are active in each cell type due to a unique epigenetic profile.

There is also good evidence to suggest that external factors (including agingenvironmental exposure, diseases like cancerdiet, and even exercise) can change the epigenetic profile, both for better and worse. A big part of what Relative Health is attempting to do is allow users to look at the relationship between changes in the epigenome and human health. 

Although epigenetics has only really been scientifically investigated in the last couple decades, the concept dates back to the early 19th century when Jean-Baptiste Lamarck suggested an idea called the inheritance of acquired characteristics. A common (but incorrect) example of this is the giraffe. Since giraffes extend their necks up to reach for food, Lamarck thought that generations that reached higher and higher into the trees for food would pass on traits for longer and longer necks. This is wrong but a reasonable assumption before biological sciences grew into what they are today.

Charles Darwin first described a biological process for the inheritance of traits in 1868 through his theory of Pangenesis. Gemmules were imagined particles of inheritance that were shed from parts of the body and traveled in the bloodstream and accumulate in the sperm or eggs. There, they would integrate with the germ cells to impact future generations - a sort of short-term evolution or adaptation. 

Until the second half of the 20th century, human developmental biology and genetics were treated as separate scientific disciplines. Conrad Waddington is credited for bringing these two fields together in 1942 and coining the term, epigenetics. The term was derived from the Greek word "epigenesis" which originally described the effects of genetic processes on human development. It was several decades later when DNA methylation was suggested to have a role in controlling gene activity, and that DNA methylation was heritable. These initial findings are now supported by a significant body of research that show DNA methylation is involved with silencing of gene activity in multiple biological systems. 

The central dogma of biology

The central dogma of molecular biology states that DNA codes for RNA, which codes for proteins. Protein is what makes up the structure of our bodies and keeps things working. DNA is, traditionally speaking, the molecule of heredity that passes from parents to offspring. As we now know, we need to broaden the definition of heredity to include epigenetics.

The central dogma of biology (DNA > RNA > Protein) needs to be rethought with what we now know about epigenetics.

Cell types are defined by specific epigenetic patterns

Cells as diverse as neurons, white blood cells, and muscle cells have unique function and morphology due to epigenetic differences, even though their underlying DNA sequence is identical. Mechanistically, the addition of methyl groups or modifications to histone proteins (two different epigenetic mechanisms) can have profound impact on gene expression and, subsequently, the phenotype of the cell.

Different cells may have identical DNA but are functionally and physically different due to different epigenetic profiles.

 

DNA methylation can change gene expression

DNA methylation is an epigenetic mechanism that can alter gene expression by binding to promoter regions and suppressing gene expression within specific genomic regions. It does this by blocking the ability of transcription factors (blue dots in the illustration below) from binding to the DNA and allowing transcription (the formation of RNA) from occurring.

DNA methylation controls gene expression by blocking transcription factor binding, thus decreasing or silencing gene activity.

Changes to epigenome can change you, physically.

If you can change the activity of a given gene, you change the amount of protein it produces. This, in term, changes your body even if it only a subtle change. For example, mice with DNA methylation at the agouti gene are obese and yellow in color, while their unmethylated counterparts have normal weight and have brown coats. Note that these two mice are genetically identical and only differ epigenetically (i.e., different DNA methylation patterns).The coat color difference relates to the expression of different types of skin pigment.  

Environment, behavior, and aging can change the epigenome

In contrast to the genome, the epigenome can be altered by several factors, and over the lifetime of an individual. Although many of the factors that can alter the epigenome are still unknown, significant evidence shows environmental exposures, stress, and aging can have a negative impact. On the other hand, positive factors such as exercise and good diet are known to change the epigenome as well! 

 

Implications of epigenetics on infertility

Several scientific studies have found that epigenetic changes are associated with male infertility. This association between epigenetic profile and infertility appears to exist even when the semen parameters (i.e., count, morphology, and motility) are normal. 

 

Implications of epigenetics on cancer

Temozolomide is used in the treatment of malignant brain tumors by damaging the tumor DNA. Methylation of MGMT gene, a gene that is important for DNA damage repair, prevents the tumor cells from repairing their DNA. Thus, DNA methylation of the MGMT gene makes it harder for cancer cells to resist treatment and patients with proper methylation have a relatively favorable prognosis to treatment with temozolomide. 

 

Implications of epigenetics on neurodevelopment

Epigenetic factors, including DNA methylation, can also impact brain development. Depending on the pattern of methylation, synapse formation can be dramatically altered. It is thought that aberrant DNA methylation may be implicated in brain disorders such as bipolar disorder, schizophrenia, and autism.

 

Epigenetic changes can be heritable 

In addition to having significant implications within an individual, epigenetic changes that occur within the gametes (i.e., sperm and eggs) may be inherited across generations. This suggests that things such as chronic stress, exposures to toxicants, and the time at which we choose to have children (i.e., aging), could have a profound impact on the health of our offspring. 

 

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