Transcription factors as master regulators of physiological and pathological processes
Decoding the genome and transcribing genetic information from DNA into messenger RNA (mRNA) are fundamental cell processes. In humans, approximately 1,600 transcription factors regulate gene transcription. The underlying mechanism involves binding of transcription factors to specific DNA sequences, known as promoters or enhancers, via their DNA-binding domains.Moreover, transcription factors recruit co-regulators, adding another level of complexity to gene transcription regulation. Further, the chromatin state also affects the function of transcription factors. Finally, the dynamics of transcription factor binding to DNA sequences modulates gene transcription.
The complex process of gene transcription regulation contributes to the differential gene expression across cell and tissue types and across developmental stages. Notably, transcription factors are involved in virtually all major cell processes, including cell division, differentiation, migration, and death as well as cell responses to environmental stimuli. Moreover, dysregulation of transcription factors has been implicated in numerous diseases, including cancer, inflammation, autoimmune disorders, cardiovascular disorders, and neurological conditions.5
What is the role of transcription factors in carcinogenesis?
Mutations or dysregulation of transcription factors can profoundly impact gene expression as well as cell proliferation, differentiation, and death and have been implicated in carcinogenesis.6 Numerous cancer types demonstrate aberrant transcription factor activity. Thus, cross-referencing 1,571 confirmed or candidate oncogenic proteins with 1,988 human transcription factors or regulators identified 294 oncogenic transcription factors and regulators. In other words, apparently approximately 19% of all known oncogenes are oncogenic transcription factors.7
What is the potential of transcription factor modulation for the treatment of cancer?
The important role of transcription factors in carcinogenesis has provoked interest in the development of cancer therapies that directly or indirectly target transcription factors. Such approaches may focus on modulating transcription factor expression, ubiquitylation and proteasome degradation, or DNA-binding activity. Further, they can affect transcription factor regulators or the interactions of transcription factors and their cofactors. An example of a drug targeting the binding of a transcription factor to DNA is mithramycin, which is an inhibitor of the transcription factor Sp1 and can displace it from the promoter regions of oncogenes.8 Another drug that has found clinical application is azacytidine, a DNA methyltransferase inhibitor, that leads to DNA hypomethylation and renewed expression of tumor suppressor genes.8
Techniques to analyze the activation and functions of transcription factors
The key role of transcription factors in physiological and pathological processes, including tumorigenesis, and the complexity of their regulation have led to active research on the establishment of techniques for their analysis. Thus, a wide range of methods have been developed to assess the function of transcription factors in vitro or in vivo.8 Traditional techniques, including electrophoretic mobility shift assays (EMSA), reporter-coupled promoter deletion assays, and transcription factor enzyme-linked immunoassays (ELISAs) evaluate the function and/or expression of individual transcription factors.
More recently, high-throughput assays for the simultaneous analysis of multiple transcription factors have also been established, including chromatin immunoprecipitation (ChIP)-chip and ChIP-seq techniques, DNA microarrays, binding site enrichment-based methods, and microfluidic devices.9 Transcription factor profiling arrays are designed to evaluate key transcription factors most frequently implicated in the regulation of cellular functions or transcription factors relevant for specific diseases or biological processes, such as oxidative stress, endoplasmic reticulum stress, cancer stem cells, and neurodegenerative conditions. Based on their characteristics, they can assess transcription factor activation, transcription factor interactions with specific factors or coregulators, or transcription factor promoter binding.
Transcription factor role in tumorigenesis and strategies for transcription factor evaluation
Transcription factors have been implicated in the pathogenesis of numerous medical conditions, including cancer, and maybe targeted for the development of therapeutic agents. Elucidating the mechanisms implicated in the complex regulation of transcription requires a comprehensive strategy for the evaluation of transcription factors’ activity and functions. A robust approach would include the assessment of both individual and multiple transcription factors in vitro and in vivo. Moreover, a comprehensive range of assays can evaluate different aspects of transcription factors’ activities and functions.
Resources
1. Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT. The human transcription factors. Cell. 2018;172(4):650-665. doi: 10.1016/j.cell.2018.01.029. Erratum in: Cell. 2018;175(2):598-599.
2. https://www.frontiersin.org/research-topics/18211/structure-and-function-of-transcription-factors-and-coregulators
3. https://www.nature.com/scitable/definition/transcription-factor-167/
4. Lickwar CR, Mueller F, Hanlon SE, McNally JG, Lieb JD. Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function. Nature. 2012;484(7393):251-5. doi: 10.1038/nature10985.
5. Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013;152(6):1237-51. doi: 10.1016/j.cell.2013.02.014.
6. Bushweller JH. Targeting transcription factors in cancer - from undruggable to reality. Nat Rev Cancer. 2019;19(11):611-624. doi: 10.1038/s41568-019-0196-7.
7. Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting transcription factors for cancer treatment. Molecules. 2018;23(6):1479. doi: 10.3390/molecules23061479.
8. Yan C, Higgins PJ. Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta. 2013;1835(1):76-85. doi: 10.1016/j.bbcan.2012.11.002.
9. Geertz M, Maerkl SJ. Experimental strategies for studying transcription factor-DNA binding specificities. Brief Funct Genomics. 2010;9(5-6):362-73. doi: 10.1093/bfgp/elq023.
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