Divyan Bavan
The human body is a network of complex systems with multiple levels of organisation. Specialised cells make up the lowest level of this hierarchy. These cells have similar genomes, organelles, and processes, but can vary from conducting electrical signals to engulfing pathogens. The explanation for this is gene regulation. This process—which is controlled by developmental pathways in precursor cells—alters the transcription of genes within the genome, allowing cells to express proteins which are specific to their function. Gene regulation is responsible for differences in cell membrane, soluble, and cytoskeletal protein expression, all of which contribute to functional specialisations in the different organs.
A major aspect of functional specialisation is defined by a cell’s interactions with its environment. This is primarily done through proteins on the cell membrane: receptors, ligands, and ion channels among others. Gene regulation is responsible for activating and repressing genes for membrane proteins, tuning expression to fit the predetermined role of the cell. In the body, there are two systems where this is especially evident—the nervous and immune systems. For the nervous system, its specialised cell is the neuron. One of its roles is processing and propagating action potentials, which requires the ability to control its membrane potential through voltage-gated, ligand-gated, and other ion channels. These channels are more heavily expressed in neurons relative to other cells (Wangzhou et al., 2021). Gene expression controls this through specific steps during neuronal differentiation. One example of this is the dissociation of the REST repressor protein, which blocks transcription of neuronal proteins in somatic cells. However, once neuronal progenitor cells differentiate into neurons, the repressor dissociates, allowing the transcription of neuron-specific genes (Ballas et al., 2005). This shows the importance of gene regulation in the composition of the cell membrane, as it directly controls the expression of critical proteins. The immune system is no different. Its T cells express special proteins called cluster of differentiation (CD) markers (Estipona, 2020). These markers can stimulate the activation of immune pathways in T cells, with different markers leading to even further specialization. For example, cytotoxic T cells selectively express CD8, a co-receptor which enables recognition of pathogens and the activation of cytotoxic pathways within the cell (Janeway, 2001). Again, this is regulated by gene expression. In thymocytes—the precursor to mature T cells—the presence of the Th-POK transcription factor leads to a thymocyte becoming a helper T cell. However, its absence, caused by expression of the Runx-dependent silencer, leads to the expression of genes required for cytotoxicity (Setoguchi, 2008). The role of Th-POK as a binary switch for cell fate in T cells highlights how gene regulation, while not the only factor, plays the largest role in cell differentiation. Through the exploration of these two systems, it is apparent that gene expression is crucial for the selective production of unique membrane proteins.
While many proteins are sent to the membrane or integrated into larger structures, many stay soluble within the cytosol. These proteins are often needed in critical processes, with gene regulation again controlling where they are expressed. One of the most documented cases of this is in the circulatory system. The major constituent of this system is the red blood cell (RBC), which transports oxygen to tissues around the body. Before RBCs fully mature and lose their nucleus, they produce vast amounts of hemoglobin: a protein which can bind to oxygen. Analysis of gene expression in RBC precursors shows that hemoglobin mRNA makes up over 95% of cellular mRNA (Kerkelä, 2022). The process behind this lies in transcription factors that are master regulators for RBC-specific genes. An example of this are the GATA1, NF-E2, KLF1, and TAL-1 complex proteins, which remodel chromatin to promote high transcription of the globin genes. In cases where this doesn’t happen, embryonic development doesn’t continue as RBCs cannot develop properly (Kim et al., 2016). This extreme regulation of gene expression shows the level of specialisation red blood cells have within the body. While hemoglobin is an intracellular protein, specialised cells also secrete various proteins. In the endocrine system, the thyroid is responsible for secreting a vast number of proteins which hormonally control several processes in the body. For example, thyroglobulin—a secreted protein which is involved in iodide processing—is specifically enriched within thyroid tissue (Uhlén et al., 2015). Similarly to RBCs, several master regulators are involved in the high expression of thyroglobulin. The transcription factors NKX2-1 and PAX8 are both heavily involved in the expression of thyroglobulin, as both proteins bind the thyroglobulin promoter (Fernández et al., 2015). Through these examples, it is apparent that the expression of genes for specialized proteins allows cells to differentiate in function. While this can occur at the molecular level with specific reactions, as seen with hemoglobin and thyroglobulin, gene expression also induces changes at the cellular level.
A cell’s shape, defined by the cytoskeleton, plays an important role in its function. This is best seen within neurons and skeletal muscle fibres. To efficiently propagate electrical impulses, neurons have evolved a unique morphology, with axons and dendrites branching out from the cell body to form synapses with other neurons. Gene regulation supports this development; upregulation of cytoskeletal genes such as β3-tubulin, although not exclusive to neurons, aid in the development and support of axons and dendrites. β3-tubulin is responsible for extending neurites: branches off the cell body. The processes behind the expression of this protein mirror the regulation of ion channels discussed earlier, with REST preventing the expression of these genes in non-neuronal cells. After REST is dissociated in neuronal precursors, transcription factors such as Sox4 and Sox11 bind to promoter regions upstream of the β3-tubulin gene, increasing expression in these cells (Bergsland et al., 2006). To further elucidate the importance of these specific constituents in neuronal function, we can look to diseases caused by defective cytoskeletal proteins. Mutations in β3-tubulin lead to several neurological syndromes, including malformations of cortical development (MCD), which are the result of improper cortical and neuronal development (Poirier, 2010). This demonstrates the importance of proper cytoskeletal gene expression, as defects in tissue-specific proteins leave gaps in their crucial roles within the cell. Skeletal muscle fibres are similar, expressing many genes critical for their cytoskeletal structure: α-actin, myosin heavy chain, dystrophin, for example. The Human Protein Atlas reports a tissue specificity score of 0.95 for myosin and 0.96 for actin (Uhlén et al., 2015) in skeletal muscle fibers, indicating that they are highly specialized for this tissue (0 represents broad expression and 1 represents exclusive expression). These proteins build the machinery necessary for the contractile motions of muscle cells, giving them their elongated, striated appearance. The production of these proteins is controlled by the master regulator gene MyoD. When this gene is expressed, it activates the expression of transcription factors which enhance the production of genes such as the myosin heavy chain, α-actin, and dystrophin. In fact, by forcing fibroblasts—a type of connective tissue cell—to express MyoD, they are converted to myoblasts, a precursor to skeletal muscle tissue (Davis et al., 1987). This illuminates how gene expression can alter the entire identity of a cell through the expression of tissue-specific genes. As seen with neuronal cells, mutations in these genes often come with severe complications. The most famous example of this in skeletal muscle tissue is Duchenne’s Muscular Dystrophy. This disease is caused by a mutation in the dystrophin protein and leads to membrane fragility and weakened muscle tissue (Venugopal, 2023). Through these results and others, it is apparent that the proper gene expression of cytoskeletal proteins plays an important role in organ function.
A cell’s membrane, soluble proteins, and morphology are highly variable, with changes in these constituents having major effects on cell function. These physical changes are made possible by the informational changes which occur within the genome. The process of differentiation, from stem cells to specialised cells, is marked by very specific changes in gene expression, indicating the central role this process plays in defining a cell’s identity. By understanding how this process works, it is possible to not only work out what makes cells unique but shift from an empirical view of physiology to a more precise, quantitative view.