Guided Search: How Transcription Factors Navigate the Genome to Change Cell Identity

Cell types express specific genes
Multicellular organisms such as humans consist of various cell types, including brain, heart, and liver cells. While these cell types have different appearances and perform distinct functions in the body, they all share the same genome. The difference among cell types arises from the way the genome is utilized. In each cell type, a specific set of genes are required for their function and are therefore activated, while the rest of genes are silenced. This cell-type-specific gene expression is controlled by how the genome is packaged inside the nucleus of cells. The genome is a very long string of DNA, about 2 meters in length, which has to fit inside the nucleus, which is about 10 microns in diameter. To achieve this tight packaging, DNA is first wrapped into beads-on-string structures known as nucleosomes, which are further condensed by other proteins to form a complex structure known as chromatin. Generally, active genes are loosely packed with nucleosomes, forming accessible chromatin structures. Silent genes on the other hand are located within inaccessible chromatin and densely-packed with nucleosomes.
Cell types converted by reprogramming factors
Cell-type-specific gene expression also require a set of proteins known as transcription factors (TFs). Each cell type uses multiple TFs in unique combinations to establish and maintain their identity. Interestingly, we can use these TF combinations to convert cells from one type to another in the lab in a process called cellular reprogramming. The most astonishing example of reprogramming is converting adult cells like skin cells into induced pluripotent stem (iPS) cells, which are similar to embryonic stem cells. These cells are very special as they can make all cell types of the body like an early embryo. The process of iPS cell reprogramming is so simple and only requires four TFs, namely OCT4, SOX2, KLF4 and MYC together known as OSKM.
Reprogramming is a powerful technology with huge potential in regenerative medicine, disease modelling, and drug discovery. We can potentially generate any cell type to repair tissues damaged by injury, disease, or ageing. For example, we could derive cardiac cells from a patient's skin cells and use them to regenerate heart tissue after a heart attack, eliminating the need for a donor and reducing the risk of immune rejection. Additionally, cellular reprogramming enables the creation of complex tissues such as "organoids" in the lab, which can serve as replacements for damaged organs or animal models. We can therefore use iPS-derived cells to study diseases and discover new treatments.
Despite the potential of cellular reprogramming, the process remains highly inefficient and often lacks specificity, which poses challenges for safe applications in clinical settings.
Reprogramming factors guided by DNA signposts
One major obstacle of of iPS reprogramming is how OSKM search and find their target genes. As stem cell genes are silenced in adult cells, OSKM need to activate these genes which are located within inaccessible chromatin. In this study, we have used a wide variety of DNA-sequencing techniques to map where OSKM bind in the genome, the positions of nucleosomes and how nucleosomes are arranged in three dimension (3D). We also measured which genes are active and which are silenced and the accessibility of chromatin during the reprogramming process.
We discovered that OSKM are often located together in the same places in the genome, but these locations change during reprogramming. Interestingly, the OSKM movement from one place to another is not random, but follows precise DNA patterns, which are orientated toward specific directions, just like "signposts". These DNA signposts are organized by how nucleosomes are arranged in 3D into chromatin fibers and loops. Guided by signposts, OSKM are funneled through chromatin loops until they find their gene targets. In fact, OSKM can be misguided to the wrong location if the direction these signposts are flipped towards the opposite way. We also investigated other TF combinations, and found that different TF combinations follow different signposts in the genome.
In conclusion, we revealed how reprogramming factors can navigate the chromatin landscape to find their target genes. This understanding will help us to improve the effectiveness of converting cells from one type to another.
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