As discussed in Chapter 6, the expression of specific genes in particular cell types or tissues is regulated by DNA sequence motifs present within promoter or enhancer elements. These elements control the alteration in chromatin structure of genes that occurs in a particular lineage, or the subsequent induction of gene transcription. It was assumed for many years that such sequences would act by binding regulatory proteins that were only synthesized in a particular tissue or were present in an active form only in that tissue. In turn, the binding of these proteins would result in the observed effect on gene expression. Indeed, as described in Chapter 6 (Section 6.3) cell extracts can be used in DNA mobility shift or DNase I footprinting assays to show that they contain protein(s) able to bind to a specific sequence.
Multiple-choice questions
Questions for Discussion
- A chromatin protein in which you have replaced the DNA-binding domain of a transcriptional activator within the DNA-binding domain from a transcription transcriptional repressor. Discuss the consequences on transcription if you overexpress the aforementioned chimeric protein in a cell.
- Suppose you swap the zinc finger domain of the estrogen receptor with that of testosterone receptors and vice versa. Then cell lines were engineered to express these receptors. Discuss the effects testosterone and hydrocortisone on these cells.
- At any given moment transcription, replication, and DNA repair are ongoing in a cell. Discuss the role of transcription factors in coordinating these processes.
- Discuss the role of RNA polymerase pausing during transcription elongation in cell survival.
- Discuss with specific examples the role of an effector molecule, homo and heteromeric protein interactions, and covalent modifications in regulating gene expression.
Further Reading
7.1 DNA binding by transcription factors
Isbel, L., Grand, R. S., & Schübeler, D. (2022). Generating specificity in genome regulation through transcription factor sensitivity to chromatin. Nature Reviews. Genetics, 23(12), 728–740. https://doi.org/10.1038/s41576-022-00512-6
Kribelbauer, J. F., Rastogi, C., Bussemaker, H. J., & Mann, R. S. (2019). Low-Affinity Binding Sites and the Transcription Factor Specificity Paradox in Eukaryotes. Annual Review of Cell and Developmental Biology, 35, 357–379. https://doi.org/10.1146/annurev-cellbio-100617-062719
Lambert, S. A., Jolma, A., Campitelli, L. F., Das, P. K., Yin, Y., Albu, M., Chen, X., Taipale, J., Hughes, T. R., & Weirauch, M. T. (2018). The Human Transcription Factors. Cell, 172(4), 650–665. https://doi.org/10.1016/j.cell.2018.01.029
Murre C (2019) Helix-loop-helix proteins and the advent of cellular diversity : 30 years of discovery genes and development 33 (1-2) 6-25.
Suter, D. M. (2020). Transcription Factors and DNA Play Hide and Seek. Trends in Cell Biology, 30(6), 491–500. https://doi.org/10.1016/j.tcb.2020.03.003
Torres-Machorro, A. L. (2021). Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix-Loop-Helix Transcription Factors. International Journal of Molecular Sciences, 22(23), 12855. https://doi.org/10.3390/ijms222312855
7.2 Activation of transcription
Antonova SV, Boeven J, Timmers HTM and Snel B. (2019) Epigenetics and transcription regulation during eukaryote diversification: the saga of TFIID genes and development 33, 888-902.
Carlsten JOP, Zhu X & Gustafsson C.M. (2013) The multitalented mediator complex. Trends Biochem Sci 38:531–537.
Field, A., & Adelman, K. (2020). Evaluating Enhancer Function and Transcription. Annual Review of Biochemistry, 89, 213–234. https://doi.org/10.1146/annurev-biochem-011420-0959165.3
Grant, P. A., Winston, F., & Berger, S. L. (2021). The biochemical and genetic discovery of the SAGA complex. Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, 1864(2), 194669. https://doi.org/10.1016/j.bbagrm.2020.194669
Jeronimo, C., & Robert, F. (2017). The Mediator Complex: At the Nexus of RNA Polymerase II Transcription. Trends in Cell Biology, 27(10), 765–783. https://doi.org/10.1016/j.tcb.2017.07.001
Papai G, Frechard A, Kolesniuoua O Crucifix C, Schultz P and Ben-Shem A (2020) Structure of SAGA and mechanism of TBP deposition on gene promoters Native 577, 711-720.
7.3 Repression of transcription
Gerber, A. N., Newton, R., & Sasse, S. K. (2021). Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era. The Journal of Biological Chemistry, 296, 100687. https://doi.org/10.1016/j.jbc.2021.100687
Machour, F. E., & Ayoub, N. (2020). Transcriptional Regulation at DSBs: Mechanisms and Consequences. Trends in Genetics: TIG, 36(12), 981–997. https://doi.org/10.1016/j.tig.2020.01.001
Mishal, R., & Luna-Arias, J. P. (2022). Role of the TATA-box binding protein (TBP) and associated family members in transcription regulation. Gene, 833, 146581. https://doi.org/10.1016/j.gene.2022.146581
Mottis A, Mouchiroud L & Auwerx J (2013) Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev 27:819–835.
Piunti, A., & Shilatifard, A. (2021). The roles of Polycomb repressive complexes in mammalian development and cancer. Nature Reviews. Molecular Cell Biology, 22(5), 326–345. https://doi.org/10.1038/s41580-021-00341-1
Timmers, H. T. M. (2021). SAGA and TFIID: Friends of TBP drifting apart. Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, 1864(2), 194604. https://doi.org/10.1016/j.bbagrm.2020.194604
7.4 Regulation at transcriptional elongation
Core, L., & Adelman, K. (2019). Promoter-proximal pausing of RNA polymerase II: A nexus of gene regulation. Genes & Development, 33(15–16), 960–982. https://doi.org/10.1101/gad.325142.119
Fujinaga, K., Huang, F., & Peterlin, B. M. (2023). P-TEFb: The master regulator of transcription elongation. Molecular Cell, 83(3), 393–403. https://doi.org/10.1016/j.molcel.2022.12.006
Kim, Y. H., & Lazar, M. A. (2020). Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space. Endocrine Reviews, 41(5), 707–732. https://doi.org/10.1210/endrev/bnaa014
Luo Z, Lin C & Shilatifard A (2012) The super elongation complex (SEC) family in transcriptional control. Nat Rev Mol Cell Biol 13:543–547.
Smith E & Shilatifard A (2013) Transcriptional elongation checkpoint control in development and disease. Genes Dev 27:1079–1088.
Wagner, E. J., Tong, L., & Adelman, K. (2023). Integrator is a global promoter-proximal termination complex. Molecular Cell, 83(3), 416–427. https://doi.org/10.1016/j.molcel.2022.11.012
7.5 Regulation of transcription by RNA polymerases I and III
Feng, S., & Manley, J. L. (2022). Beyond rRNA: Nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis. Genes & Development, 36(15–16), 876–886. https://doi.org/10.1101/gad.349969.122
Hori, Y., Engel, C., & Kobayashi, T. (2023). Regulation of ribosomal RNA gene copy number, transcription and nucleolus organization in eukaryotes. Nature Reviews. Molecular Cell Biology, 24(6), 414–429. https://doi.org/10.1038/s41580-022-00573-9
Watt, K. E., Macintosh, J., Bernard, G., & Trainor, P. A. (2023). RNA Polymerases I and III in development and disease. Seminars in Cell & Developmental Biology, 136, 49–63. https://doi.org/10.1016/j.semcdb.2022.03.027