Genetics, Epigenetic Mechanism

Article Author:
Nora Al Aboud
Article Author:
Hafsa Shahid
Article Editor:
Ishwarlal Jialal
Updated:
9/16/2020 1:49:10 PM
PubMed Link:
Genetics, Epigenetic Mechanism

Introduction

Epigenetics is the study of the machinery involved in the regulation of gene expression that occurs without changing the DNA sequence. "Epi" is Greek for "above," therefore, meaning modifications above the genes or on the genes. Epigenetic changes arise through DNA base modifications and changes to the superstructure of DNA packaging. DNA Packaging is covered through a different StatPearls review.

Briefly, 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 nucleosomes that appear as beads on a string under the electron microscope. 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.[1] This organized DNA protein complex allows the cells to regulate what something expresses genes. When histone proteins in nucleosomes are modified, the cell’s DNA replication and transcription machinery can either more easily or less easily access the DNA, thus changing gene expression patterns. Epigenetic modifications are not permanent but many persistent, even through generations. Epigenetic changes can be influenced by several factors including age, environment, and particular disease state.

Function

Epigenetics forms a layer of control within a cell that determines which genes are turned off and which genes are turned on. This control varies from tissue-to-tissue and cell-to-cell. Epigenetic regulation of a cell is made possible by chemical modifications of DNA or histone proteins and not to the sequence of the DNA. Every cell has the same DNA, but every cell has a different function. 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 so their expression of genes is vastly different from an infection fighting cell in the blood. Every cell has its specified function, and that specified function is determined by which genes are on and which genes are off. 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. 

Three different epigenetic mechanisms have been identified including: DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing. DNA methylation involves the addition of a methyl group directly to a cytosine residue within a cytosine-guanine sequence or (CpG) sequence. For example, multiple CpG sites make up a CpG island. CpG islands are frequent sites for DNA methylation along cytosine residues. If the cytosine is methylated within a promoter region, the gene is silenced and not expressed. Direct DNA methylation at cytosine residues turns off genes. The addition of these methyl groups to cytosine is controlled tightly within cells and is carried out by enzymes called DNA methyltransferases.

The second epigenetic modification is histone protein modification. Histone changes occur post-translationally on histone tails that protrude from nucleosome structures, allowing for “reading” of these marks by epigenetic machinery. When the machine reads that a certain gene has different combinations of epigenetic tags, it will either cause the gene to be expressed or silenced. Each of these tails have various points at which different chemical signals are added. There are different chemicals that can be added to the tails resulting in acetylation, methylation, phosphorylation, ubiquitylation, and sumoylation.[2] 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. The Histone Code is reviewed in a different StatPearls article.

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 lncRNA. 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 (less than 30 nucleotides (nt)) 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 of the potential to turn genes on and off without changing the underlying DNA sequence, which is much harder. There are drugs approved for human use or are under development which alter the methylation patterns of the DNA or adjust histone modifications. Despite not altering the DNA, this machinery is complex with many mysteries as to how the same genes are involved in gene expression in many different tissues. Treatment must be selective, targeting the specific cells a researcher is attempting to affect; otherwise, modifying the wrong genes in different cells may cause adverse consequences.

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, as determined by the Dutch famine studies.[2][3] 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. Furthermore, cancer research has identified the epigenetic machinery to be involved in oncogenesis, thus many epigenetic modifying drugs are under development to treat cancer’s abnormal epigenetic regulation and thus cancer development and progression.

Within inheritable genetic disease, a growing list of disorders involves congenital epigenetic syndromes or those due to a genetic defect in the genes encoding the actual epigenetic machinery. These syndromes include Rubinstein Taybi Syndrome, Kabuki Syndrome, Menke Hennekam Syndrome, KAT6A syndrome, Nicolaides-Baraitser Syndrome, Coffin-Siris syndrome, and many others. Additionally, several mental retardation disorders such as Fragile X, Prader-Willi, and Angelman syndromes are associated with changes in DNA methylation leading to disease pathology, despite their molecular origins being either chromosomal or a triplet repeat.

Enhancing Healthcare Team Outcomes

Increased understanding of epigenetic mechanisms of disease will allow us to understand its role in disease pathophysiology and progression. If we are able to modify epigenetic marks and ultimately control gene expression, both acquired disease, like cancer, and congenital disease, like Rubinstein Taybi syndrome, may have more direct and effective treatment options.  Individuals with congenital epigenetic syndromes have complex medical needs and require coordination of care to ensure adequate communication between team members to prevent known co-morbidities and complications.


References

[1] Allis CD,Jenuwein T, The molecular hallmarks of epigenetic control. Nature reviews. Genetics. 2016 Aug     [PubMed PMID: 27346641]
[2] Heijmans BT,Tobi EW,Stein AD,Putter H,Blauw GJ,Susser ES,Slagboom PE,Lumey LH, Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the United States of America. 2008 Nov 4;     [PubMed PMID: 18955703]
[3] Tobi EW,Lumey LH,Talens RP,Kremer D,Putter H,Stein AD,Slagboom PE,Heijmans BT, DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Human molecular genetics. 2009 Nov 1;     [PubMed PMID: 19656776]