Transcription factors and human health
Transcription factors are essential proteins that regulate gene expression by influencing the transcription of DNA into messenger RNA (mRNA), which is the first step in protein production. They bind to specific DNA sequences, called promoters or enhancers, to activate or repress the transcription of genes. They are crucial for the control of a wide range of biological processes, including cellular development, response to external stimuli, and maintenance of cellular homeostasis. Alterations in the function of transcription factors are associated with numerous diseases. Proper regulation of gene expression is essential for embryonic development, immune response, metabolism, and other physiological functions. Defects in transcription factors can lead to:
Genetic diseases: Mutations in genes that encode transcription factors can lead to inherited diseases. For example, mutations in the FOXP2 gene are associated with language and learning disabilities.
Metabolic disorders: The transcription factor PPAR-γ is crucial for regulating lipid and glucose metabolism. Defects in its function may contribute to obesity, type 2 diabetes, and cardiovascular disease.
Inflammatory diseases: Factors such as NF-κB regulate inflammation. Its excessive activation is associated with chronic conditions such as rheumatoid arthritis and other autoimmune diseases.
Role of transcription factors in gene expression
Transcription factors act in specific ways to control gene expression:
Activation: Some transcription factors promote gene expression by binding to regulatory regions of DNA, facilitating the recruitment of RNA polymerase and the initiation of transcription.
Repression: Other factors can repress gene expression by blocking the access of RNA polymerase to DNA or by recruiting other proteins that inhibit transcription.
Spatiotemporal regulation: These factors ensure that genes are expressed at the right time and in the right tissues during development and response to specific signals.
Transcription factors and the immune system
Transcription factors play a critical role in regulating the immune system, orchestrating the activation, differentiation, and function of immune cells. They act as molecular “switches” that activate or repress the expression of specific genes in response to environmental or internal signals. Proper functioning of these factors is essential for maintaining immune homeostasis, while their deregulation can contribute to the development of autoimmune diseases and inflammatory disorders.
Role of Transcription Factors in the Immune System
Transcription factors are involved in all phases of the immune response, from the maturation of immune cells to the regulation of inflammation. Here are the main factors and their specific roles:
NF-κB: is one of the most studied transcription factors in the context of innate and adaptive immunity. It regulates the transcription of pro-inflammatory genes, cytokines, chemokines, adhesion molecules and proteins involved in the immune response. NF-κB is rapidly activated in response to pathogens via Toll-like receptors (TLRs) and other signaling pathways, promoting the production of cytokines such as TNF-α, IL-1β and IL-6, which are crucial for acute inflammation and defense against infections. NF-κB is also important for the survival, proliferation and differentiation of T and B lymphocytes, being activated by stimuli such as binding of the TCR (T cell receptor) or BCR (B cell receptor). Chronic overactivation of NF-κB has been linked to several autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). In these conditions, uncontrolled activation of NF-κB leads to chronic inflammation and tissue damage.
STATs (Signal Transducer and Activator of Transcription): Members of the STAT family are crucial for the transduction of cytokine-mediated signals and for the regulation of lymphocyte differentiation.
STAT1: Regulates the response to interferon (IFN-γ) signals and controls the antiviral and antimicrobial immune response.
STAT3: It is involved in the differentiation of Th17 lymphocytes, a subset of CD4+ T cells that plays an important role in immunity against extracellular pathogens and in the pathogenesis of autoimmune diseases. Excessive activation of STAT3 can lead to an increase in Th17 cells, which are implicated in the pathogenesis of diseases such as multiple sclerosis (MS), psoriasis and rheumatoid arthritis.
STAT6: Involved in the differentiation of T cells into Th2, which are crucial for immune responses against parasites. However, excessive activation of STAT6 is associated with allergic diseases such as asthma and some autoimmune diseases.
FOXP3 and the regulation of regulatory T cells (Treg): FOXP3 is a key transcription factor for the development and function of regulatory T cells (Treg), which are essential for maintaining immune tolerance and preventing autoimmune responses. Tregs suppress the activation and proliferation of effector T cells, preventing inappropriate immune responses against self-antigens. Mutations in the FOXP3 gene cause severe autoimmune disorders, such as Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome (IPEX), which is characterized by high autoimmune activity and systemic inflammation.
GATA3 and Th2 cell differentiation: GATA3 is the master transcription factor that regulates the differentiation of type 2 helper T cells (Th2), which are involved in immune responses mediated by cytokines such as IL-4, IL-5, and IL-13. These cytokines are essential for the production of IgE antibodies, but their excess is associated with allergic and autoimmune diseases, such as asthma and atopic eczema.
T-bet and Th1 cell differentiation: T-box transcription factor is the master transcription factor that promotes the differentiation of Th1 cells, which are crucial for immunity against intracellular pathogens, such as viruses and bacteria. T-bet regulates the expression of IFN-γ, a pro-inflammatory cytokine essential for macrophage activation. Dysregulations of T-bet may contribute to autoimmune diseases such as type 1 diabetes, where an excessive Th1 cell response leads to the destruction of pancreatic beta cells.
RORγt and Th17 cell differentiation: This is the key transcription factor for the differentiation of Th17 cells, which produce pro-inflammatory cytokines such as IL-17 and IL-22. Th17 cells play an important role in defense against extracellular fungi and bacteria, but are also implicated in numerous autoimmune diseases. Excessive activity of RORγt and Th17 cells is associated with diseases such as multiple sclerosis, psoriasis and psoriatic arthritis, where IL-17-mediated inflammation causes tissue damage.
Transcription factors and cancer
Transcription factors play a key role in carcinogenesis, as they control genes involved in growth, differentiation, and apoptosis (programmed cell death). When dysregulated, they can contribute to tumor development and progression in several ways:
Mutations in transcription factors. Mutations that increase the activity of oncogenic factors (for example, MYC, a potent transcription activator) can promote uncontrolled cell proliferation.
Epigenetic alterations. Chromatin modifications that affect the access of transcription factors to DNA can result in dysregulation of gene expression and promote tumor growth. For example, p53 is a well-known tumor suppressor, and its inactivation in many cancers leads to a loss of control over cell growth.
Interaction with growth signals. Transcription factors such as STAT3 and AP-1 are activated by signaling pathways that promote cell growth and survival; the best known are calcium-lipid-dependent protein kinases (PKC) and mitogenic protein kinases (ERK1, ERK2, ERK5). Their overactivation is a common feature of many types of tumors.
Plasticity and metastasis. Transcription factors play a key role in epithelial-mesenchymal transition (EMT), a critical process for the acquisition of the ability of tumor cells to invade and metastasize by reverting to a stage of inverted maturity (dedifferentiation to the embryonic stage). Twist, Snail and Slug are examples of factors involved in EMT.
Role of transcription factors in carcinogenesis
Many transcription factors are key components of signaling pathways that control cell growth and survival. When these signaling pathways are overactivated, transcription factors can become constitutively active, contributing to cancer. An example is STAT3 (Signal Transducer and Activator of Transcription 3), which is normally activated in response to cytokines such as Interleukin-6 (IL-6). Once activated, STAT3 translocates to the nucleus and activates genes that promote cell proliferation and survival. Overactivation of STAT3 is common in many solid tumors and has been shown to promote tumor growth, angiogenesis (formation of new blood vessels), and invasiveness. Similarly, NF-κB is a transcription factor that regulates inflammation, immune response, and cell survival. Its chronic activation has been associated with various cancers, as it contributes to resistance to apoptosis and tumor growth. However, scientists agree that the master regulator for carcinogenesis must be Activator Protein 1 (AP-1), which is composed of members of both c-Fos and c-Jun proteins. It regulates genes like cyclins (Cyclin A1, Cyclin D1, Cyclin E and others) necessary for cell cyle progression.
Epigenetic deregulation and chromatin accessibility
Transcription factors work in synergy with epigenetic modifiers (e.g., histone deacetylases or methyltransferases) to control DNA accessibility and its transcription. Epigenetic modifications, such as histone acetylation and methylation, influence how transcription factors access target genes. Epigenetic deregulation can alter the activity of transcription factors and promote cancer. For example, hypermethylation of the promoter of the p16 gene, which encodes a cyclin D inhibitor, reduces its expression, promoting cell cycle progression and, consequently, uncontrolled proliferation. Many tumors respond to environmental signals such as hormones, growth factors, or cytokines, which activate oncogenic transcription factors. For example, in breast cancers that express the estrogen receptor (ER-alpha), this transcription factor regulates the expression of genes associated with cell growth and division. Anti-cancer therapies such as tamoxifen aim to block the activation of this factor, thereby inhibiting tumor growth.
Transcription factors and drug resistance
An emerging area of research is the involvement of transcription factors in drug resistance. Cancer cells often develop resistance to targeted therapies through the deregulation of transcription factors. For example, FOXO3a, a pro-apoptotic transcription factor, is often inactivated in drug-resistant cancer cells, allowing them to avoid cell death even in the presence of chemotherapeutics. STAT3 is also implicated in chemotherapy resistance, as it promotes the survival of cancer cells in response to drug-induced stress by allowing the synthesis of proteins that protect against apoptosis (such as the famous Bcl-2). There are several STAT3 inhibitors both used in the laboratory and under investigation in clinical trials for the treatment of cancer. One of these is napabucasin, which is in phase 3 clinical trials for colorectal cancer, while C188-9 and AZD9150 are being investigated against pancreatic cancer.
Therapeutic Strategies Targeting Transcription Factors
Manipulating transcription factors to restore drug sensitivity is a promising field for the development of novel therapeutic approaches. Therapeutic approaches targeting transcription factors are challenging, as these proteins tend to have flat surfaces without easily accessible pockets for traditional drugs. However, some innovative approaches have been developed, as most known transcription factors do not have clear-cut, defined molecular “pockets” into which to introduce an inhibitor or modulator. This is the case for MYC inhibitors: although it is difficult to directly target MYC, research is underway on molecules that interfere with the protein-protein interactions involved in its activation. In the case of the p53 tumor suppressor, strategies to reactivate p53 in tumors where it is mutated include compounds such as RETRA, SCH529074, PRIMA-1 and APR-246 (eprenetapopt), which stabilize the mutated protein restoring its tumor suppressor function.
Summary
Transcription factors are central players in the regulation of both innate and adaptive immune responses. They control the production of all the proteins that each organ needs to perform its functions. Alterations in their function can lead to the development of autoimmune diseases, in which the immune system attacks healthy tissues of the body. Defects in their function that appear in embryonic or fetal age can alter the brain structure, with serious consequences for physiology and cognitive and behavioral functions. Understanding the molecular mechanisms of these factors offers new opportunities for the development of targeted therapies in autoimmune diseases, neurological diseases, tumors and other human pathologies.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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