Genetics, Epigenetic Mechanism

Article Author:
Nora Al Aboud
Article Editor:
Ishwarlal Jialal
Updated:
12/2/2018 12:50:47 PM
PubMed Link:
Genetics, Epigenetic Mechanism

Introduction

Epigenetics is the study of heritable changes in gene expression that happen without involving any changes to the basic DNA sequence, which ultimately results in a change in the phenotype without a change in the genotype. Epigenetic changes can be influenced by several factors including age, environment, and particular disease state. There are over 100,000 cells in one square centimeter of tissue, and each of these cells contains close to 2 meters of DNA that contain our genetic information. The genetic material in our body is called a genome. DNA is  packaged with proteins known as histones. The DNA and protein complexes are known as chromatin. DNA is wrapped around histone proteins forming repeated units of nucleosome that look like beads on a string. Chromatin is condensed further to form a chromosome. Humans have 46 chromosomes stored in the nucleus. The core of one nucleosome is composed of DNA wrapped around a histone octamer that consists of 2 copies of the major types of histones H2A, H2B, H3, and H4. This organized DNA protein complex allows the cells to regulate what something expresses genes.[1]

Function

Epigenetics forms a layer of control that determines which genes are turned off and which genes are turned on in particular cells in the body. They do this by making chemical modifications of chromosomal DNA and/or structures that change the pattern of gene expression without altering the DNA sequence. Every cell has the same DNA, but every cell has a different function, and the expression patterns of genes are different in each particular cell type. For example, enzyme secreting cells in the intestinal epithelial help break down food. Every cell has its specified function, and that specified function is determined by which genes are on and which genes are off.

All the cells in our body from skin cells, muscle cells, and liver cells contain the same DNA sequence yet; these cells have different structures and functions. This variation and structure in different cells are because only certain genes are expressed within each cell the DNA. Furthermore, the histones can be tagged by tiny chemicals that modify gene expression, these chemical tags cause some genes to be turned on, and some genes turned off. If there were no epigenetic tags, there would be chaos, and the body would not be able to develop a complex interacting system of tissues and organs. For example, muscle cells will have genes turned on that a muscle cell requires and will turn off genes that a liver cell requires; similarly, the liver cell will have genes for muscles turned off and genes that a liver requires turned on. These modifications are known as epigenetic modifications. "Epi" is Greek for "above," therefore, meaning modifications above the genes or on the genes. Epigenetic modification causes lasting changes in gene expression. In a normal human cell, the genetic material is made of the DNA is wrapped around nucleosomes, which are made up of histone proteins. Histone tails come off the histone proteins.

DNA is a combination of 4 nucleotides: G for guanine, C for cytosine, A for adenine and T for thiamin. There are at least 3 different epigenetic mechanisms that have been identified including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing. The first one is DNA methylation in which a methyl group is added directly to a cytosine residue that exists in a cytosine-guanine sequence (CpG). For example, many CpG sites make up a CpG island, and the cytosine is methylated. The methylation of CpG sites in promoter regions is associated with gene silencing. DNA methylation turns off genes. The addition of methyl groups is controlled in cells and is carried out by enzymes called DNA methyltransferases.

The second epigenetic modification is histone modification and is usually a post-translational modification of histone proteins. This takes place on the tails of the histone proteins that form that nucleosome. They help form that nucleosome; therefore, each of these histone proteins has a tail that sticks out the side. Each of these tails has various points at which different chemical signals are added making epigenetics complex. There are different chemicals that can be added to the tails resulting in acetylation, methylation,  phosphorylation, ubiquitylation[2],and sumoylation . The position of each of these tags on the tail and whatever is lying next to it greatly influence what these particular chemical tags do; therefore, histone modification is complex, but overall, acetylation opens the DNA allowing for expression. For example, Histone3K9 acetylation correlates with transcription activation, while Histone3k27 trimethylation correlates with transcription repression. Genome-wide patterns of DNA and histone modifications or epigenome are established during early development and are maintained during cell division. In cancer, these patterns are altered and disrupted. Thus, histone modifications are involved in transcriptional activation/inactivation, chromosome packaging, and DNA repair. 

The most recently studied epigenetic mechanism is non-coding RNA-associated gene silencing. A noncoding RNA or ncRNA is a functional RNA molecule that is transcribed from DNA but not translated into proteins. Some of those identified include miRNA, siRNA, piRNA, and lnc RNA. These ncRNAs regulate gene expression or silencing at the transcriptional and post-transcriptional level. Those ncRNAs that appear to be involved in epigenetic processes can be divided into 2 main groups; the short ncRNAs (les than 30 nts) and the long ncRNAs (greater than 200 nts). The 3 major classes of short non-coding RNAs are microRNAs (miRNAs), short interfering RNAs (siRNAs), and piwi-interacting RNAs (piRNAs). Both major groups are shown to play a role in heterochromatin formation, histone modification, DNA methylation targeting, and gene silencing.

Epigenetics is one of the promising future areas of research because it theoretically, it is simpler to turn genes on and off than to change DNA sequence. Some drugs have been approved for human use or are under development to alter the methylation patterns of the DNA or adjust histone modifications. Treatment needs to be selective, targeting the specific cells for which a researcher is looking; otherwise, modifying the wrong genes in specific cells may cause adverse consequences. Epigenetics is a promising and emerging field of medical research which may influence the way people develop and manage disease.

Issues of Concern

As people age, the biggest influences on the epigenome is the environment. Direct influences such as diet can affect one's epigenome. A person who has a healthy diet will have different epigenetic pattern than somebody who has an unhealthy diet. The epigenome can also be influenced by indirect environmental changes, for example, stress.

Clinical Significance

One example of how nutrition influences the epigenome is found in queen and worker bees. These 2 are genetically identical. The only difference is that queen bees are force-fed royal jelly from the larval stage, and the worker bees are fed nectar, pollen, and water. This royal jelly diet switches on genes in the queen. This leads to the queen developing ovaries and a large abdomen for laying eggs. These varied diets switch on particular genes, and the queen develops ovaries while the worker bees remain sterile.

Cancer was the first human disease to be linked to epigenetics. Studies performed by Feinberg and Vogelstein demonstrated that genes of colorectal cancer cells were hypomethylated compared with normal tissues. Also, several mental retardation disorders such as Fragile X, Prader-Willi, and Angelman syndromes are associated with changes in DNA methylation.

Enhancing Healthcare Team Outcomes

The epigenome is changeable; therefore, when things happen, and genes that are inactive must be expressed, they can be altered. This is particularly important during development. The cells are listening for signals to change DNA expression. The signals may come from inside the cell, neighboring cells, or the environment.

Increased understanding of epigenetic mechanisms of disease and gene editing technologies will allow us to understand its role in disease regulation and aid in diagnosis and targeted therapies of many clinical diseases.