Is It All About DNA, or Is There More to the Story?
- Kader Gül Odabaş
- Feb 5
- 6 min read
The human body develops into a complex structure, starting from a single cell. The genetic information we possess at birth defines our physical characteristics and biological limitations. Many features, from our eye color to our skeletal structure, are encoded in our DNA. However, these codes are not read in the same way throughout life. Genetics offers a potential field; epigenetics influences under what conditions and to what extent this potential will manifest. Therefore, we do not remain as we are at birth. Life experiences, environmental conditions, and cellular needs determine which parts of the genetic information will be active.
The term epigenetics refers to the regulatory mechanisms that operate on genetic information. It encompasses systems that influence when and to what extent genes are expressed without altering the DNA sequence. Factors such as diet, stress, sleep patterns, and physical activity can play a role in these regulatory mechanisms. However, epigenetics does not "rewrite" genetics; it operates within genetic boundaries.
Genetics is like a library in the center of the cell, containing ancient knowledge passed down through generations. Epigenetics, on the other hand, is like an attendant who controls which category of book is opened and read when. One of the most frequently used analogies when explaining epigenetics is nutrition. Genetically advantageous traits you possess (for example, easily developing muscles, having thick hair, or being creative) can emerge thanks to epigenetics. You might have long, slender legs and a strong breath to be a very good runner; that is, you are genetically predisposed to it. But if you don't eat properly, take care of your mind, and never try running one day, your genetic potential becomes meaningless. Genetics and epigenetics are interconnected; if one exists, the other is also possible.
If we think of genetics in terms of how many rooms a house has and how large it is, then how we furnish and use the interior of that house can be defined as epigenetics. In other words, even if the basic structure of a house is small in terms of square meters, its interior design or layout can make it appear larger or more spacious. Redesigning a house doesn't change its fundamental architectural features; it doesn't make the walls thicker or the windows bigger, but it can highlight existing advantages and create a different atmosphere. Similarly, epigenetic modifications don't change the basic structure of genetics; they only shape how genes are expressed and don't create a permanent change in genetic information.
This is our DNA in its simplest form. Its full name is deoxyribonucleotide acid. It is composed of four nucleotides: adenine, thymine, guanine, and cytosine, in a flexible yet tightly interlocked structure. It is aware that it holds precious information, which is why it maintains a central, hard-to-decipher code and protective mechanisms. With its four different letters (nucleotides), it's a dense and impressive novel, full of verses. However, not every page is accessible at any time. Someone needs to open and read that page.
When storing information, our DNA wraps around a protein called a histone , reducing the space it occupies. This close embrace saves space while also making the DNA harder to unwrap, thus keeping the information more secure. This packaged unit of DNA wrapped around histone proteins is called a nucleosome. Nucleosomes fold closer together, forming chromatin fibers and eventually the famous chromosome. Therefore, before reaching the helical structure of DNA, this collective embrace with histone proteins must be loosened. Thanks to this association between histone proteins and DNA, information is protected, and the timing of which gene is read and when is controlled.
This is where the epigenetic aspect comes into play, the process of unraveling this sweet embrace. It's here that the decision is made on which parts of the DNA will be wrapped around histone proteins and which regions will be identified as active genes. The histone-DNA relationship doesn't happen randomly; the biggest factor is the laws of biophysics. AT-rich regions of DNA are more flexible, while GC-rich regions are more rigid. This allows histone proteins to more easily attach to the most flexible points of the DNA. Furthermore, the positive charge of histones and the negative charge of DNA create a strong electrostatic match between them. While these two structural features enable them to bind together, they don't provide much specificity; the real difference lies with chromatin regulatory proteins. Chromatin regulatory proteins like SWI/SNF, ISWI, CHD, and INO80 can shift, remove, and reposition the nucleosome (DNA-histone complex) using ATP. In addition, modifications to histone tails (H3K4me3, H3K27ac, etc.) regulate which regions of the chromatin are accessible. Some DNA-binding proteins (such as FOXA, GATA, and PU.1) are strong enough to bind to histone-wrapped DNA regions and facilitate their unwrapping. Chemical modification of histones directly affects the tightness of this wrapping. Histone acetylation, in particular, occurs at positively charged lysine residues and weakens DNA-histone interaction. Chromatin relaxes, DNA becomes more accessible, and transcription is facilitated. Therefore, acetylation marks such as H3K9ac and H3K27ac are often found in active gene regions. Histone methylation, however, does not have a one-way effect. For example, H3K4 methylation is associated with gene activation, while H3K27 trimethylation is associated with gene repression. Phosphorylation mostly plays a role in stress situations such as DNA damage responses, while histone ubiquitination can both increase and repress gene expression depending on the location and number of histones to which it binds.
The activation or complete silencing of a gene within a cell is not a random process. These decisions are made by finely tuned regulatory systems called epigenetic mechanisms. Epigenetics can be thought of as an overlay that controls gene expression without altering the DNA sequence. This overlay decides which genes will “speak” and which will remain silent, taking into account the cell’s environment, needs, and identity. Another important aspect of epigenetic control is DNA methylation. DNA methyltransferase enzymes can repress gene expression by adding a methyl group to the cytosine base in cytosine-guanine (CpG) sequences. CpG sequences are usually found as CpG islands, and these islands are often located in the promoter regions of genes. DNA methylation in the promoter region facilitates the binding of repressor proteins, limits the access of transcription factors to DNA, and promotes heterochromatin formation. As a result, the gene is silenced.
In recent years, non-coding RNAs have also emerged as an integral part of the epigenetic network. MicroRNAs, siRNAs, and long non-coding RNAs fine-tune gene expression by interacting with DNA methylation and histone modifications. It is becoming increasingly clear that these RNAs contribute to heterochromatin formation and play critical roles in maintaining cellular identity.
All these mechanisms work together to explain why cells with the same genetic information acquire different identities. Some epigenetic marks are preserved throughout cell divisions; thus, the cell continues to “remember” who it is over time.
Resources and Suggested Readings:
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