Transcription factors (TFs) are proteins that regulate gene transcription, the process of synthesizing mRNA from DNA. TFs bind to specific DNA sequences adjacent to the genes they regulate by its DNA-binding domain (DBD). These proteins uniquely bind to DNA at promoter or enhancer regions. When a TF binds to an enhancer region, it can either activate or inhibit gene transcription. Promoter sequences, situated at the gene's 5' end, serve as the transcription start site where the transcription initiation complex assembles. In contrast, enhancers or regulatory sequences may be situated distally to the gene being transcribed. TFs function to regulate gene expression, ensuring genes are activated or repressed in the appropriate cells, at the correct times, and in the right amounts throughout the cell's and organism's lifespan. The activity of TFs is crucial in determining cell differentiation fate.
Fig.1 Overview of TFs.1
The TFs expressed by different cell types, such as:
| B cell: Bcl-6, IRF4; | Macrophage/monocyte: c-Jun, CREB, IRF5; | Conventional DC: SPI1, STAT5; | Th2: c-MAF, Ikaros; |
| Mature/follicular/ germinal center B cell: BACH2, Pax-5; | M1: NF-κB p65, STAT1; | Monocyte-derived DC: IRF4, SPI1; | Th9: NF-κB p65, STAT6; |
| Marginal Zone B/memory B/B1 cell: IRF8, SPI1; | M2: CREB, STAT6; | T cell: TCL1, ZAP-70; | Th17: ROR γ, T-bet; |
| Short lived plasma cell (SLPC): Blimp-1, XBP-1s; | Dendritic cell: BATF, GFI1; | T follicular helper: IRF4, STAT5; | Th22: AHR, STAT3; |
| Breg: Blimp-1, IRF4; | Plasmacytoid dendritic cell: IRF7, NFIL3; | Th1: STAT1, T-bet; | Treg: Smad3, T-bet; |
TFs execute their functions within the cell nucleus, where genes are situated, and their nuclear import or export can modulate gene activity. A crucial mechanism for regulating TF activity is phosphorylation. Additionally, TFs can regulate the transcription of other TFs, as well as their own genes, resulting in intricate feedback control mechanisms. TFs participate in various physiological processes, including development, immunity, and stress responses. Analyzing TF expression, activity, regulation, and gene sequences can aid researchers in elucidating the significance of their roles in disease processes.
Fig.2 Regulation of gene transcription in mammals.2, 3
Basal Regulation
In eukaryotes, a crucial class of TFs known as general transcription factors (GTFs), including TFIIA, TFIIB, and TFIID, are essential for transcription initiation. Most GTFs do not directly interact with DNA; instead, they are integral components of the extensive transcription preinitiation complex that directly interacts with RNA polymerase. This complex associates with promoter regions upstream of the genes under regulation.
Differential Enhancement of Transcription
Additional TFs modulate gene expression through interaction with enhancer sites on DNA proximal to the genes under their influence.
Cells communicate by releasing molecules that trigger signaling cascades in recipient cells. When these signals require the activation or repression of genes, TFs frequently participate downstream in the signaling cascades.
Environmental stimuli prompt signaling cascades, wherein TFs operate downstream to regulate gene expression. Notable examples include heat shock factor (HSF) and hypoxia-inducible factor (HIF).
Many TFs in multicellular organisms are integral to development. These factors respond to stimuli by turning on or off the transcription of specific genes, facilitating changes in cell morphology or activities necessary for cell fate determination and differentiation (e.g., Hox, SRY).
TFs can also modify gene expression in host cells to promote pathogenesis, such as TAL effectors.
Numerous TFs, particularly those functioning as proto-oncogenes or tumor suppressors, regulate the cell cycle, influencing cell size and the timing of cell division (e.g., Myc).
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