Saturday, 12 July 2014

Context and architecture: Complexities of the genome

Most people are aware that deoxyribonucleic acid, or DNA, encodes the information that controls the development and function of all living organisms. This information is organised into regions called genes and the complement of DNA information that exists in any organism is known as its genome.

In complex multicellular organisms such as humans, the genome is a database of master plans for the entire body. But more than a decade since the human genome was decoded, several fundamental questions regarding genome regulation remain largely unanswered.

What controls the development of more than 200 distinct cell types from this single source of genetic information? How are genes that serve special roles in the pancreas or brain prevented from being ‘switched on’ in other organs? And why does the activity of some important genes change in diseases such as cancer and diabetes?

We now know that these questions cannot be answered solely by understanding the DNA code. The exciting field of epigenetics is at the frontier of research into the essential processes that control genes and how these differ between cell types under normal and disease conditions.

Genes: the master plans for life
At the simplest level, genes provide instructions for the construction of proteins.

Because proteins are fundamental to a vast array of processes that govern life, reading and correctly decoding the biological information written in genes is critical to normal cell function. To do this, cells possess decoding hardware that turns the information stored in genes into messenger transcript molecules composed of ribonucleic acid (RNA). Proteins can then be constructed by using the information in the RNA as a template.

The amount of any given protein is primarily controlled by the amount of RNA that can be made from the corresponding gene. In this way, genes can be viewed as the master plans for the construction of a building. RNA messenger transcripts are the intermediate copies of these plans that can be taken off site, while proteins are the final products or buildings. Although in other cases, the RNA molecules themselves can be the final product.

DNA (genes) codes for RNA molecules that are templates for protein synthesis.
n some cases, the RNA is the final, functional product        

One genome, many cell types
Humans and other animals are composed of many different cell types that form distinct organs and tissues.

Despite this remarkable variation, all cells within the body are derived by cell division from a single origin - the fertilised egg - and therefore contain identical DNA . Each cell type requires access to only a certain combination of master plans (gene program) to fulfil their job.

For example, expression of specific genes by immune cells causes them to look and behave entirely differently to kidney, nerve, or red blood cells. The immune cell accesses a gene program that encodes proteins required to defend the body against infection, whereas nerve cells only access genes needed to be a nerve cell.

Accessing the wrong gene programs can cause severe developmental and biological consequences. It is therefore critical that a cell activates (switches on) and maintains the correct gene programs while simultaneously silencing (switching off) unwanted genes.

But how do cells achieve this selective process with the necessary precision? Numerous scientific studies have shown that the physical shape and organisation of the DNA is central to the control of gene expression.

All cells within the body contain identical DNA because they are derived
by cell division from the fertilised egg

The complex organisation of DNA
Each cell contains around two meters of DNA that needs to be compacted within a microscopic nucleus.

Unlike a lot of popular descriptions, DNA does not exist in the cell as long, free-floating strands. In fact DNA wraps around small proteins called histones like thread on a spool, allowing it to be organised and packaged with remarkable efficiency. This combination of DNA and histones (as well as other small proteins) is called chromatin.

The key to gene activation is the interaction between decoding hardware and the DNA. Interruption of this process effectively silences the gene by preventing RNA from being made.  So when DNA is loosely associated with histones, genes are accessible to the decoding hardware and can therefore be ‘switched on’. On the other hand, genes are ‘switched off’ when the DNA is tightly wrapped around histones, mostly because they become buried within the chromatin structure.

Chromatin conformation and DNA accessibility are central to gene expression

Tagging the chromatin for gene expression
Only recently have scientists begun to truly understand how chromatin transitions between ‘on’ and ‘off’ states.

Research has found that small chemical tags can be attached to histone proteins or directly to the DNA itself. Importantly, addition or removal of these tags controls how dense or loosely the DNA wraps around histones. This means they can also control which genes are switched on or off by guiding when and where the decoding hardware can perform its role.

Because these chemical tags can regulate changes in gene expression independently of the DNA sequence, they are called epi-genetic (above or over the genome). Collectively, epigenetic tags comprise the epigenome. While all cells within the body effectively have the same genome, the epigenome determines the gene program and therefore the cell type.

The discovery and characterisation of a vast array of epigenetic modifications has revolutionised the study of genetics, developmental biology, and human disease. Unique patterns of epigenetic tags are established for each cell type early in the process of differentiation from a fertilised egg. These epigenetic patterns closely correspond to different gene programs and are stably maintained through cell division.

However, changes to epigenetic tags can have considerable consequences for a cell because this alters the gene program. For example, abnormal gene silencing caused by the distortion of epigenetic patterns has been linked with developmental disorders as well as several types of cancer. Changes to the epigenome can also accumulate with time and have been proposed to contribute to ageing.

Epigenetic changes can regulate transitions between on and off states of gene expression    

Epigenetics and human disease
Recent years have witnessed a rapid increase in the epigenetic analysis of human diseases, with numerous studies finding that the environment of the cell can greatly influence epigenetic patterns and therefore gene regulation.

Factors including smoking and nutrition have been shown to change the epigenetic tags on genes that are associated with the development and progression of human diseases.

Prime examples are the specific epigenetic changes linked with the abnormally high blood sugar levels experienced by people with diabetes. Recent findings suggest that these changes could drive some of the secondary effects of diabetes including heart disease, blindness, and kidney failure. And the fact that some epigenetic tags persist over the long term may explain why diabetic patients can continue to develop secondary complications many years after they have controlled their blood glucose.

A rapid increase in the number of epigenetic studies associated with human disease in the past 10 years. Source: NCBI PubMed search terms 'epigenetics' and 'human disease' 

The language of the genome
Two main factors determine if a gene is switched on or off.

First the DNA encoding a gene must be unwound from histone spools to allow the decoding hardware to gain access. Second, the decoding hardware must turn the information stored in the gene into RNA so the final protein product can be made. Patterns of epigenetic tags sit on top of the genome and direct the activation or silencing of genes by allowing the chromatin to unwind or condense. Different patterns regulate different gene programs that give rise to many different cell types from the same genome. 

The epigenome can be thought of as the grammar that provides context for the language of DNA. In the same way that grammatical errors can cause the intended message of a sentence to be lost, tight control of the epigenome is central to the way genetic information is expressed by cells. This control can be affected by environmental factors, altering gene programs that contribute to the development and progression of disease.

Many researchers anticipate that understanding how specific genes are epigenetically altered in diseases such as diabetes, heart disease, and cancer may provide new avenues for more effective therapy.

While significant progress has been made in recent years, the characterisation of epigenetic changes in human diseases remains a formidable challenge for biologists.


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1 comment:

  1. 23andme delivers mildly interesting news about your % of neanderthal DNA and 5th cousins you didn't know about. But the story becomes riveting if you go to ancillary sites that process your raw genetic data (GeneticGemie, NurtraHacker, KnowYourGenetics) and find woeful news of homozygous genetic mutations that hold a key to health problems, like malfunctioning methylation pathways. Overwhelming for those w/o scientific backgrounds, raising a sudden need for genetic literacy. Your article is a perfect primer on epigenetics, the "grammar that provides context for the language of DNA".