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Epigenetics


Overview

Even though we are all human, why do some of us have blonde hair or darker skin? Why do some of us hate the taste of mushrooms or eggplants? Why are some of us more sociable than others? 

As an organism grows and develops, carefully orchestrated chemical reactions activate and deactivate parts of the genome at strategic times and in specific locations. Epigenetics is the study of these chemical reactions and the factors that influence them. Epigenetics technically is the study of heritable changes in chromatin (e.g., DNA methylation) without involving a change in DNA sequences.

Our DNA is a huge data bank. It is like a library with 6 million books. If the library doors are closed and locked, the library is of no use. Epigenetics is the study of the mechanisms that take down the appropriate book, read it, then implement what is there. Or conversely, the mechanism may block a book from being read! DNA is tightly wound and not of any value in that state. Lets say you need more of a certain protein. Something has to identify where in the DNA the blueprint is to make that protein, open up the DNA, make the necessary copy of the appropriate string (and ignore certain areas), then close and repack the DNA. Epigenetics is the study of how that works.

The Epigenome

The epigenome is a multitude of chemical compounds that can tell the genome what to do. 

The human genome is the complete assembly of DNA (deoxyribonucleic acid)-about 3 billion base pairs - that makes each individual unique. The base pairs are C-G and A-T. 

Among the chemical compounds is what is called a methylation tag (I will call the tag "Met"). DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites–that is, where a cytosine is directly followed by a guanine in the DNA sequence). This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. 

Simply put, as the DNA is unwound in order to get to the sequence for duplication desired, a tag is placed where the start and finish points where duplication is NOT wanted! Removal of these tags allows the duplication.

Histone acetylation also enhances transcription while histone deacetylation represses transcription.

Gene Control and Cancer

Cancer develops when a cell becomes abnormal and begins to grow out of control. Cancer can begin when mutation changes a cell's DNA sequence. But cancer cells can also have abnormal epigenomes. In many cancers, some genes are turned up and some are turned down -- often in the very same cells.

Cancer is just one of a growing number of diseases that are being linked to abnormalities in the epigenome. Out of control growth leads to cancer by both turning off genes coding for proteins that slow cell growth, and turning on genes coding for proteins that speed up cell growth.

Cancer cells have a lower level of methylation than healthy cells. Too little methylation (missing Met tags) results in:

    .  Allowing activation of genes that promote cell growth.

    .  Causing chromosome instability: highly active DNA is more likely to be duplicated, deleted, and moved to other locations.

Cancer cells can also have genes that have more methyl (have a "turn off" Met where it is not supposed to be) than normal. The types of genes that are turned down in cancer cells:

   .  Keep cell growth in check (not available)

   .  Repair damaged DNA (not available)

   .  Initiate programmed cell death (not available)

Researchers are exploring drug therapies that can change the epigenetic profiles of cancer cells. One challenge with epigenetic therapies is figuring out how to target drugs to the right genes in the right tissues.

Epigenetic Tags

Epigenetic tags (Met's) act as a kind of cellular memory. A cell's epigenetic profile (the epigenome) -- a collection of tags that tell genes whether to be on or off -- is the sum of the signals it has received during its lifetime. Signals from the outside world can work through the epigenome to change a cell's gene expression. Met's can be added or removed by conditions outside the entity. 

Epigenetic Activity at the Beginning of Life

As a fertilized egg develops into a baby, dozens of signals received over days, weeks, and months cause incremental changes in gene expression patterns. Epigenetic tags record the cell's experiences on the DNA, helping to stabilize gene expression. Each signal shuts down some genes and activates others as it nudges a cell toward its final fate. Different experiences cause the epigenetic profiles of each cell type to grow increasingly different over time. In the end, hundreds of cell types form, each with a distinct identity and a specialized function.

Even in differentiated cells, signals fine-tune cell functions through changes in gene expression. A flexible epigenome allows us to adjust to changes in the world around us, and to learn from our experiences.

Early in development, genes are "poised" like runners in the starting blocks, ready to jump to action.

In a differentiated cell, only 10 to 20% of the genes are active. Different sets of active genes make a skin cell different from a brain cell.

Environmental signals such as diet and stress can trigger changes in gene expression. Epigenetic flexibility is also important for forming new memories.

Changes to the Epigenome

The epigenome changes in response to signals. Signals come from inside the cell, from neighboring cells, or from the outside world (environment). 

Early in development, most signals come from within cells or from neighboring cells. Mom's nutrition is also important at this stage. The food she brings into her body forms the building blocks for shaping the growing fetus and its developing epigenome. Other types of signals, such as stress hormones, can also travel from mom to fetus.

After birth and as life continues, a wider variety of environmental factors start to play a role in shaping the epigenome. Social interactions, physical activity, diet and other inputs generate signals that travel from cell to cell throughout the body. As in early development, signals from within the body continue to be important for many processes, including physical growth and learning. Hormonal signals trigger big changes at puberty. These changes to the epigenome are kept in the egg or sperm!

Even into old age, cells continue to listen for signals. Environmental signals trigger changes in the epigenome, allowing cells to respond dynamically to the outside world. Internal signals direct activities that are necessary for body maintenance, such as replenishing blood cells and skin, and repairing damaged tissues and organs. During these processes, just like during embryonic development, the cell's experiences are transferred to the epigenome, where they shut down and also activate specific sets of genes.

Gene Silencing in the Egg and Sperm

For most genes, we inherit two working copies -- one from mom and one from dad. Depending on the gene, either the copy from mom or the copy from dad is epigenetically silenced. Silencing usually happens through the addition of methyl groups (Mets) during egg or sperm formation. The genes that are not silenced are called imprinted genes. For a female child, one of the two X copies has Mets placed on it's length so it will not be used, it then is compacted and put aside.

The epigenetic tags on imprinted genes usually stay put for the life of the organism. But they are reset during egg and sperm formation. Regardless of whether they came from mom or dad, certain genes are always silenced in the egg, and others are always silenced in the sperm.

There are ~25,000 genes in humans but not all are used at same time in all cells. Epigenetics is concerned with this regulation. It is the "comments" and "import" statements in the code base of DNA.

~1000 genes are involved in epigenetic control



Good references

http://www.web-books.com/MoBio/Free/Ch7F2.htm#methylation

https://www.whatisepigenetics.com/i-am-no-longer-haunted-by-that-awful-memory-new-epigenetic-drug-treatment-may-erase-painful-memories/

https://www.wehi.edu.au/wehi-tv/x-inactivation-and-epigenetics

http://www.economist.com/node/21552168

https://www.whatisepigenetics.com/histone-deacetylation-turns-cancer-protecting-cells-into-cancer-killing-cells/

 


   


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