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The 3D structure and regulation of DNA inside the cells

The human genome, our genetic blueprint, is a complex and intricate code that contains all the instructions for building and maintaining the functioning of every cell in our bodies. Traditionally, it was thought that the coding regions of the genome (the complete DNA of an organism), the ones containing genes that will end up giving proteins, were the only important parts of our DNA. However, over the past few decades, the non-coding genomes, which are the parts of our genetic material that do not code for proteins, previously known as junk DNA, have gained importance due to their regulatory roles. In this article, we will explore the fascinating world of the non-coding genome and delve into its three-dimensional organization to shed light on its vital role in shaping our biology.


The Non-coding Genome and its Regulatory Function

The human genome contains more than 20,000 genes that will produce proteins. These genomes, however, only constitute a small portion of the entire human genome (approximately 2%) (The ENCODE Project Consortium 2012). The rest of the genome is known as the non-coding genome, which includes non-coding regulatory elements that we will explain later, such as promoters, enhancers, transposable elements, and non-coding RNAs. (Figure 1) (Pagni et al. 2022). Once considered "junk DNA" (Ohno 1972), they are now seen as a key part of our genetic material with crucial functions in controlling gene expression and the complex processes that occur within our cells. While all the cells of our body contain the same genetic information, not all cells express the same genes at the same time, and this is due to tight control of their expression through different regulatory mechanisms.

Figure 1. Most of the human genome corresponds to non-coding sequences (Fu 2018).

One of the primary roles of the non-coding genome is to regulate the gene expression in each cell. 5 to 10% of the human genome is transcribed into RNAs, however, most of them will not produce proteins, being ncRNAs (Figure 1). Inside those, the microRNAs, which can bind to messenger RNAs (mRNA), to avoid their protein production, are the most studied ones (Esteller 2011). Regarding the non-coding regulatory elements that are not transcribed (converted into RNA), there are many different kinds, including promoter, enhancer, and silencer regions. Promoters are located at the beginning of the gene sequences and act as switches to activate their transcription, depending on the binding of different regulatory proteins to their regions (Figure 2) (Haberle and Stark 2018). Enhancers can also activate gene expression, but in contrast with promoters, they can be located distally to the genes they regulate, even when just a few megabases away in the linear genome. Despite their physical separation from the gene starting points, they have the ability to physically interact with their target genes thanks to the three-dimensional organization of the genome (Figure 2) (Karpinska and Oudelaar 2023). Silencers have the opposite effect to enhancers; they are also distal regulatory elements but, in this case, they can suppress or reduce gene expression (Riethoven 2010). By controlling the activity of silencers, enhancers, and promoters, cells can fine-tune gene expression levels so they can properly function in different situations.

Figure 2. Enhancers and promoter regions regulate gene expression (Zhang 2021).

The 3D Organization of the Genome

Despite the linear length of the genome measuring more than 2 meters when stretched out, it is intricately packed into a compact space of fewer than 5 micrometres in the nuclei of the cell. Avoiding a tangled mess and adopting specific organizational 3D structures is key for the proper functioning of each cell type (Szalaj and Plewczynski 2018).


Our genome is condensed in the nucleus forming chromosomes, of which humans have 46. Those chromosomes are already arranged in specific regions inside the nucleus, known as chromosome territories (Figure 3). Inside a chromosome territory, we can distinguish between A and B compartments (Figure 3), which are associated with open (active compartments with genes being transcribed) or closed regions (inactive compartments with repressed genes) of the genome (Fortin and Hansen 2015). This spatial segregation of genes into different compartments provides an additional layer of control over gene regulation, ensuring that genes with similar functions or expression patterns are co-regulated and functionally coordinated.


Then, the DNA is subsequently divided into functional units known as topologically associating domains (TADs) (Figure 3). TADs can be thought of as little neighbourhoods within the DNA that contain genes and their regulatory elements that physically interact with each other (da Costa-Nunes and Noordermeer 2023). Within these TADs, there are special structures called loops. These loops act like bridges, bringing together enhancer elements with their target genes (Figure 3). These loops enable precise and controlled regulation of gene expression by facilitating the interaction between distal enhancers and their corresponding genes. By looping together, enhancers and silencers can physically contact the genes they regulate, allowing for efficient communication and fine-tuning of gene activity (Rao et al. 2014).

Figure 3. The 3D genome is organized at four levels, including chromosome territories, A/B compartments, TAD, and chromatin loops (Yang 2022).

It is important to consider that the 3D organization of the genome is not static, in contrast, it is really dynamic and it changes continuously in order to adapt to the needs of the cells in different moments of development or to face different situations and stresses. The changes to the 3D structure ensure the appropriate gene activation or silencing at the right time and in the appropriate cellular context (Zheng and Xie 2019).


Implications in Health and Disease

Alterations in the non-coding DNA and its 3D organisation can disrupt the normal functioning of the cell by disrupting gene regulation, leading to different disorders and diseases. There are a lot of genetic variants associated with diseases, such as cancer or developmental disorders, that occur within the non-coding regions (Zhang and Lupski 2015), and those not only affect gene expression but also the 3D organization of the genome. For instance, a mutation in a regulatory element might cause a gene to be inappropriately activated, leading to uncontrolled cell growth that could result in cancer.


By unravelling the 3D organization of the genome and the non-coding regions, key players involved in disease processes can be identified. Those may end up being biomarkers or therapeutic targets that were unknown until now (Kishore and Karunagaran 2022; Matsui and Corey 2017). This knowledge opens up opportunities for the development of targeted therapies such as precision medicine. Precision medicine is an approach that aims to tailor medical treatments to individual patients by identifying specific genes and regulatory elements involved in particular diseases. This targeted approach has the potential to be more effective and have fewer side effects than traditional treatments (König et al. 2017). Furthermore, studies of the 3D organization and the non-coding regions can also shed light on the mechanisms of drug resistance. Many diseases, such as cancer, can become resistant to treatments over time (Zhang et al. 2021). By understanding how changes in the genome's organization contribute to drug resistance, strategies to overcome or prevent it can be created, improving patient outcomes.


Conclusions

The non-coding genome, previously considered an unimportant part of our genome, and known as junk DNA, has gained a lot of attention during recent decades as a critical component of our genetic code. Its regulatory elements, together with its three-dimensional organization, add a new layer of complexity to gene regulation that is key to understanding how our genome works. By unravelling the functions of this part of our DNA, we have started gaining valuable insights into human development, disease processes, and potential biomarkers and therapeutic targets. The study of the non-coding genome and its 3D organization has paved the way for future advancements in understanding gene regulation that may contribute to different areas, including precision medicine.


Bibliographical References

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Pagni, S., Mills, J.D., Frankish, A., Mudge, J.M., and Sisodiya, S.M. (2022). Non-coding regulatory elements: Potential roles in disease and the case of epilepsy. Neuropathol. Appl. Neurobiol. 48, e12775. https://doi.org/10.1111/nan.12775


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Visual sources

Cover Image: 3D genome organization – How cancer cells re-organize the 3D structure of their DNA? 2021. [Image]. Tech Explorist. Retrieved June 22th, 2023, from https://www.techexplorist.com/how-cancer-cells-re-organize-3d-structure-dna/38978/ Figure 1: Most of the human genome correspond to non-coding sequences. Fu (2018) [Image]. Single-Cell Non-coding RNA in Embryonic Development. Adv Exp Med Biol. Retrieved June 22th, 2023, from https://link.springer.com/chapter/10.1007/978-981-13-0502-3_3 Figure 2: Enhancers and promoters regions regulate gene expression. Zhang (2021) [Image]. EPIsHilbert: Prediction of Enhancer-Promoter Interactions via Hilbert Curve Encoding and Transfer Learning. Genes. Retrieved June 22th, 2023, from https://www.mdpi.com/2073-4425/12/9/1385 Figure 3: The 3D genome is organized at four levels, including chromosome territories, A/B compartments, TAD, and chromatin loops. Yang (2022) [Image]. Machine Learning Methods for Exploring Sequence Determinants of 3D Genome Organization. Journal of Molecular Biology. Retrieved June 22th, 2023, from https://doi.org/10.1016/j.jmb.2022.167666



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