Written by:

What is going on inside a living thing is very complex. Take note of how humans differ in appearance. These are the outcomes of a person's genetics, diet, lifestyle, and geographical environment. Under each causal stratum, a more complex mechanism can be discovered. Our genetic differences are the ultimate source of our differences. The DNA that is contained within our cells acts as a blueprint for how an organism  look, what advantages and disadvantages it should have, and how the body should react to external changes such as food, medication, temperature, contaminants, and so on. It can copy itself through a process called DNA replication. This ensures all the cells, the smallest unit of living things, have all the necessary instructions to carry out all the biological processes. A surprisingly small portion of our DNA contains these instructions that tell our bodies how to make things. These are known as genes. 

Genes typically contain instructions for producing proteins, which are indispensable to all biological processes. The messenger RNA (mRNA) transports these instructions from the DNA inside the cell to the ribosomes, where the ribosomes translate them into proteins. The proteins will generate the necessary products for all cellular and extracellular life processes. One could compare a cell to an automotive factory. You cannot build a car by hand from inception; you will need the appropriate machinery to form the car's body, manufacture its components, and assemble the vehicle. Most critically, a car-building plan is required. DNA is the blueprint for the car, mRNA is the instruction manual for the machines that manufacture the car, and ribosomes are the factory engineers who construct the machines that manufacture the car. The machine's output is a completely functional automobile. This is the central dogma of molecular biology as introduced by Francis Crick, who was awarded the Nobel Prize in 1962 for elucidating the structure of DNA. This transformation from DNA to protein is known as gene expression.

Several decades later, scientists have uncovered numerous mechanisms that regulate gene expression within the cell. A protein called histone can modify the structure of DNA by packaging and unravelling it through a process known as chromatin remodeling, which is essential for regulating the level of gene expression, i.e., the amount of its product that is produced. When DNA becomes more densely wound, it becomes more difficult for the machinery that converts DNA to mRNA to access it. When the DNA unravels, the gene becomes accessible, allowing for the transcription of mRNA. The machinery is called transcription factors. mRNA transcription is carried out by RNA polymerase, which is recruited by a transcription factor. You can think of transcription factors as a chief engineer writing a document containing work instructions (mRNA) on how to manufacture a car, and RNA polymerase as the pen and paper he used. However, in biology, there are transcription factors that activate DNA transcription (termed activators) and factors that inhibit the process (called repressors). A further layer of complexity is added by the fact that transcription factors can be regulated by processes such as phosphorylation and methylation, which affect their activity. Moreover, since transcription factors are proteins, their production in cells, i.e., gene expression, can be regulated by the cell itself.

However, the mRNA is not easily translated into proteins. Non-coding RNAs (ncRNAs) regulate the quantity of mRNA that is translated into proteins between the processes of mRNA transcription and mRNA transport to the ribosomes for translation. They are referred to as non-coding because, although they are transcribed from DNA, they do not code for a protein. Examples of ncRNAs that regulate the amount of mRNA translation are microRNAs (miRNAs) and small interfering RNAs (siRNAs). The miRNAs and siRNAs bind to parts of the mRNA based on complementary sequences. These bindings would be broken apart via a process called mRNA degradation, or access to the ribosomal RNA would be blocked, preventing gene translation.

The appeal of regulatory RNAs stems from the fact that they can regulate the level of gene expression rather than simply turning it on or off. From a scientist’s perspective, the complexity of gene expression allows for fine-tuned modulation of a specific biological process of interest. Through genetic modification techniques, this manipulation of gene expression can be achieved by controlling the histone packaging, manipulating the number of activators or repressors of the transcription factors, and recruiting regulatory ncRNAs. This knowledge is applicable to broad fields. Scientists involved in medicine (gene therapy), agriculture (crop and livestock improvement), and diverse biotech companies (bioproducts from microbes, environmental clean-ups, etc.) have a wealth of molecules relating to gene expression that they could harness to produce desirable traits or results from their products or treatments. Most importantly, this knowledge humbles us, as, despite significant progress in our understanding of the gene expression system, we are still only scratching the surface. 

Bibliography

1. CRICK, F. Central Dogma of Molecular Biology. Nature 227, 561–563 (1970).

2. Hombach, S. & Kretz, M. Non-coding RNAs: Classification, Biology and Functioning. Advances in Experimental Medicine and Biology 3–17 (2016) doi:10.1007/978-3-319-42059-2_1.

3. Clapier, C. R. & Cairns, B. R. The Biology of Chromatin Remodeling Complexes. Annual Review of Biochemistry 78, 273–304 (2009).