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What is genomics?
Our Executive Perspectives are informational primers intended for executives and functional leaders. They are intended to provide a calculated mix of technical and commercial understanding of relevant topics in science and technology industries.
Overview
Epigenetics has become a cornerstone of genomics and remains a growing field in cancer therapeutics (among other areas such as cardiac health and wound healing). This primer seeks to provide an overview of the key topics related to epigenetics as well as its commercial relevance.
What is Epigenetics?
Epigenetics is the study of changes in an organism’s response to modifications or gene expression rather than the genetic code – more commonly referred to as phenotypic variations (gene-based variations are referred to as “genotypic”).
Three of the most common methods that alter how the gene is expressed without altering the underlying DNA include DNA methylation, histone modification and RNA-associated silencing.
What is Transcription?
To understand epigenetics, one has to first understand the fundamentals of DNA replication. This process starts with Transcription[1], which is the process by which DNA is copied into RNA (messenger or mRNA). RNA polymerase is the enzyme that is used to transcribe DNA into RNA. Once transcribed into RNA, the ribosome is used to translate RNA information into amino acids and terminates when the ribosome interacts with a termination codon (UAG, UAA, UGA). Once formed, amino acid chains are folded into protein structure through a process called post-translational modifications.
At this point, it is worth noting the differences between genotypic variations and phenotypic variations. Genotypic variations are a direct result of differences in the genetic code whereas phenotypic variations occur as a result of what happens with the genetic code. For instance, due to environmental circumstances, an organism may activate or deactivate certain genes.
What is DNA Methylation?
The process of DNA methylation includes adding a methyl group (CH3) to the 5 carbon location on cytosine – creating a 5-methylcytosine (5-mC). Because of the frequency with which these 5-mC are found in the genome, this 5-mC has been unofficially labeled a “Fifth Base Pair”.
DNA methylation is commonly found among mammalian DNA[2] and up to 80% of CpG dinucleotides. DNA methylation is highly researched because when it occurs at CpG islands, which are largely NOT methylated regions of the DNA sequence, it can lead to silencing (or turning off) the tumor suppression genes found in cancer cells[3].
What is a CpG Island?
When cytosine is located next to a guanine on a DNA strand, they are bound together with phosphate (note this is a different bond than when nucleotides across from each other bind – these nucleotides use Hydrogen bonds). Within a 200 basepair DNA sequence, if more than 50% of the base pairs are CpG, it is considered a CpG island. While most CpG sites are heavily methylated, CpG Islands remain largely unmethylated. When the Cytosine on these CpG islands are methylated, it increases the risk of spontaneous mutations[4], which may result in cancer. There are approximately 30,000 CpG islands in the human genome[5].
What are TET Enzymes?
Recently discovered, TET (ten-eleven translocation) enzymes[6] have been found to aid in the de-methylation process or the removal of methyl groups from cytosine. This reversal of cytosine methylation is promising in turning tumor suppressor genes back ON – thus stopping cancerous genes from replicating.
What is Histone Modification?
Histones are proteins found inside chromatin (inside the nucleus) that bind DNA giving it a tight, condensed structure that fits inside the cell nucleus. Histone Modification refers to a type of “post-translational modification” that folds the protein structure via methylation, acetylation and phosphorylation[7]. When histones are modified in the cell nucleus, specific genes within the histone may be activated or silenced.
What is RNA-Associated Silencing?
RNA-Associated Silencing refers to ability of RNA to turn on or off specific genes. RNA plays a crucial role in the transcription and translation process of converting DNA into proteins. In this process, certain genes coded by RNA may not be translated into genes.
What is Bisulfate Sequencing?
The traditional method of analyzing the genome for methylation is bisulfite sequencing but it is considered a harsh process that changes the chemical makeup and physical properties of DNA[8]. Bisulfite sequencing is a process that treats cytosine (non-methylated) such that the Cytosine converts to Uracil. The process leaves methylated cytosine (Fifth Base Pair or 5-mC) untouched. The chemical treatment process results in several DNA strand breaks including highly fragmented single-stranded DNA.
The length of the treatment often converts the unmethylated cytosine into uracil, however the resulting genomic data is degraded such that it can no longer be amplified using PCR. With less aggressive treatments, researchers run the risk of overestimating methylation as the sample detection may read many unmethylated cytosines that were not converted as they should have been.
There is a great need for alternative methods that can provide better quantification of methylation in the genome that is not as destructive nor as misleading as bisulfite sequencing.
Advances in Epigenetics
Recent advances in epigenetics include the reduced cost of genome sequencing combined with increased knock-out gene capabilities that turn genes ON/OFF, However, software algorithms are being developed that look at genome-wide DNA methylation to analyze genomic data and attempt to provide information that may be used in clinical trials to determine patient’s responsiveness to certain treatments (better known as bioinformatics).
Trends
Epigenetics is inextricably linked to the area of genomics research, which continues to evolve. There are several trends that have emerged over the past decade in response to new technologies or discoveries worth noting: NGS, Knock-Out Genes, Companion Diagnostics and liquid biopsies.
- Knock-out genes: with technologies such as CRISPR and ZFN, the ability to knock out individual genes that may cause disease has armed scientists with a new tool to fight against disease
- Companion diagnostics: while not necessarily new, the recent discoveries have created a renewed focus on ensuring that therapies are effective within the individual rather than the many.
- Liquid biopsies – the ability to read biomarkers in blood and urine. Advancements in epigenetics has made it possible to avoid painful and difficult extractions from tissue biopsies by using biomarkers released in body fluids.
- Bioinformatics and computational genomics are exploding. Epigenetics is a large, untapped market opportunity for software solutions that is just starting to gain traction.
Insight
Epigenetics is a burgeoning field of research where scientists have barely scratched the surface. However, with more data, increased access to data and the advances in search algorithms, machine learning and artificial intelligence – bioinformatics and computational genomics will lead the way in providing answers to root causes such as immuno-oncology therapies and preventative measures.
By: Kiran Chin
REFERENCES
[1] https://www.britannica.com/science/transcription-genetics
[3] https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070
[4] https://en.wikipedia.org/wiki/DNA_methylation
[5] https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cpg-island
[6] https://www.ncbi.nlm.nih.gov/pubmed/24153300
[7] https://www.whatisepigenetics.com/histone-modifications/
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865059/pdf/gkl1134.pdf
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