In molecular biology and genetics, a transcription factor (sometimes called a sequence-specific DNA-binding factor) is a protein that binds to specific DNA sequences, thereby controlling the flow (or transcription) of genetic information from DNA to mRNA. Transcription factors perform this function alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes.
Currently, over 300 of the about 1,600 TFs encoded by the human genome have been linked to at lrast one disease phenotype. However, drugs are not available for most of these TFs due to their inrinscially disordered structure and lack of binding pockets for small molecules. Recent advances have shown that many aspects of TF function can potentially be targeted for disease treatment, such as ligand binding, DNA binding, dimerization, protein-protein interactions, stability, cofactors, expression, activity and signaling pathways involving the TF. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
Transcription facts have broad effects that can be unique and pleiotropic by cell type, development stage, and disease state. Because of the varying effects, clear genetic linkages to disease with transcription factors are challening. For example, a transcription factor may have a role in normal embryonic brain development, yet later in life, cause liver inflammation and exacerbate type 2 diabetwe. Transcription factors can regulate dozen or even hundreds of genes. These regulatory effects differ by cell type, development stage, disease stage and more.
Transcription Factors Important in Immune Function:
The immune system requires many layers of positive and negative regulation to elicit effective resposnes against pathogens, while preventing autoimmunity and damage assocaited with extended inflammation. This regulation is controlled at multiple levels including transcription, mRNA processing and stability, protein stability, and post-translational modification. Transcription is one of the main levels of this regulation and controls the expression of cytokines, inflammatory mediators and immune response genes, some of which are upregulated hundreds of fold. Aberrant TF expression, expression of specific TF isoforms, or present of TF variants can lead to dysregulation of immune signaling pathways and the development of immune related diseases. For example, hmans are known to express two distinct isofroms of FOXP3 due to alternative splicing, the principal isoform cotnaing all coding exons and a shorter isoform that omits exon 2 during splicing. Pateints expressing only the shorter isoform have been found to develop autoimmunity due to regulatory T cell instability. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
TF families involved in regulation of immune gene expression:
There are several major TF families that are known to be heavily involved in the regulation of immune gene expression, including NF-kappabeta, STATE, interferon Regulatoyr Factor (IRF), activating Protein-1 (AP-1), Nuclear (NRs) and Nuclear Factor of Activated T cells (NFAT). Members form these families regulate both distinct and overlapping target genes, which allows for crosstalk between the pathways. For example, Ts form all of these families have been found to regualte the expression of the pro-inflammatory cytokines IL17A, IL1B and TNF. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–NF-kappabeta: is a family of inducible TFs, consisting of the prtoeins p50, p52, c-Rel, p65 (RelA) and RelB, that play majory roles in both innate and adaptive immune respoens. A key feature of the NF-kB family members is that they homo and herodimerize to form transcriptionally active complexes, with 15 possible dimers, all with somewhat different DNA specificites and transcriptional activities. In unstimulated cells, NF-kB dimers are sequestered in the cytoplasm by IkB proteins. Upon stimulation by pathogen ligands and pro-inflammatory cytokines, signaling to NF-kB dimers occurs thorugh either the canoical or non-canonical pathway. In the canonical pathway, the IkBs are phosphorylated by IKKbeta, leading to theri degradation via uiqutination, allowing p50-p65 dimers to translocate to the nucleus. In the non-canonical pathway, IKKalpha phosphorylates the NK-kB subunit p100, resulting in its proteasomal processing to p52 and activation of p52-Rel dimers. both patways lead to the binding of NK-kB dimers to kB sites in enhances and promoters to induce transcription of specific target genes. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–STATs: The STAT family of TFs consists of seven members: STAT1-6. STATE1 and sTAT2 are invovled in the prtoection against viral and bacterial infection through signaling from interferon (IFN) receptors. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–IRFs: The IRF TF family members are essential in antiviral and antibacterial immune respoens as they act downstream of pathogen ligands and cytokines, as well as in immne cell differentiation. Humans express nine of the known IRFfamily homologes, IRF1-9, all of which are involved in innate immunity and some also have roles in adaptive immunity. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–AP-1: is a fmaily of basic luecin zipper TFs consisting of 4 subfmailies, Jun (c-Jun, JunB, JunD), FOS, ATF and MAF and NRL that form homo and heterodimers. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–Nuclear receptors (NRs): are a superfamily of 48 ligand dependent TFs containing 4 subfamilies based on their ligand binding proeprites: steroid receptors, RXR heterodimers, homodimeric orphan receptors and monomeric orphan receptors. Steroid receptros (type I receptors) such as flucocoricoid receptor, estrogen receptor, and androgen receptor bind steroid ligands which is reuqired for their activaiton and interact with DNA mostly as homodimers. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).
–Nuclear factor of activated T-cells (NFAT): is a TF family expressed in most immune cells that plays a key rol in immune regulation, particularly in adaptive immunity. (Bass, “Transcription factors in the development and treatment of immune disorders” Transcription, 2025, 16(1), 118-140).