10.11:
Combinatorial Gene Control
The expression of most genes is regulated by more than one transcription factor, with many genes being turned on or off using different combinations of proteins. This combinatorial gene control allows eukaryotes to precisely control transcription.
Combinatorial gene control can regulate whether a gene is transcribed, as well as its transcriptional efficiency. Consider three transcription factors, A, B, and C, which affect the transcription of a gene, X.
If A is absent, gene X will not be transcribed. If C is absent, gene X will not be transcribed. And if B is absent, transcriptional efficiency will decrease. Therefore, the combination of all three regulators is necessary for high levels of transcription of gene X.
A transcriptional regulator can participate in the regulation of multiple genes. A along with B and C cause the transcription of gene X, but A along with another transcription factor, D, can stimulate the transcription of a different gene, Y. This allows a few transcription factors to regulate a large number of genes.
Transcription factors are classified into different families and can function synergistically either with other proteins from the same family or with those from different families.
Transcription factors belonging to the POU family regulate genes with a variety of functions, ranging from housekeeping to cell differentiation; however, there are very few proteins in this family, with just fifteen in humans.
Their ability to perform their diverse functions depends on their coordination with other transcription factors from different families.
Combinatorial gene control is necessary for the in vitro reprogramming of differentiated cells. Expression of the transcription factors Oct-4, Sox-2, Klf-4, and c-Myc in somatic cells can trigger conversion to stem cells.
Reprogramming does not occur in the absence of any of the first 3 proteins, and the absence of c-Myc results in low-efficiency reprogramming. The combinatorial control of all four factors is necessary for the formation of induced pluripotent stem cells.
10.11:
Combinatorial Gene Control
Combinatorial gene control is the synergistic action of several transcriptional factors to regulate the expression of a single gene. The absence of one or more of these factors may lead to a significant difference in the level of gene expression or repression.
The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene expression occurs through these proteins working with each other in various combinations to regulate the expression of different genes.
Combinatorial gene control occurs through several different mechanisms. In yeast, three different mechanisms have been described. In the waiting-activating system, all of the transcription factors required to regulate the expression of a gene bind to the DNA and only activate transcription when they receive a signal. For example, transcription factors that regulate genes needed in the late G1 phase of the cell cycle bind to the regulatory site of their target genes in early G1. However, they induce transcription only when a cyclin-protein kinase is activated in the late G1 phase.
In joint-phase combinatorial control, the transcription factors required primarily for a particular phase of the cell cycle remain attached to the regulatory sequence throughout the cell cycle and participate cooperatively in the regulation of genes during other phases. For example, SBF and Fkh2 are two transcription factors that are primarily involved in the regulation of genes that need to be expressed in G1 and G2 phases respectively. However, certain essential genes that need to be expressed in S-phase are also regulated by the combined action of SBF and Fkh2.
The joint-process combination involves the use of a single transcription factor aided by different combinations of other transcription factors for the regulation of different cellular processes. For example, transcription factors that regulate the expression of genes needed in the G1 phase of the cell cycle, also participate in the regulation of genes required for the mating process in association with a different set of regulators.
Suggested Reading
- Reményi, A., Schöler, H. R., & Wilmanns, M. (2004). Combinatorial control of gene expression. Nature structural & molecular biology, 11(9), 812-815.
- Qi, H., & Pei, D. (2007). The magic of four: induction of pluripotent stem cells from somatic cells by Oct4, Sox2, Myc and Klf4. Cell research, 17(7), 578-580.
- Godini, R., & Fallahi, H. (2019). Dynamics changes in the transcription factors during early human embryonic development. Journal of cellular physiology, 234(5), 6489–6502. https://doi.org/10.1002/jcp.27386
- Kato, M., Hata, N., Banerjee, N., Futcher, B., & Zhang, M. Q. (2004). Identifying combinatorial regulation of transcription factors and binding motifs. Genome biology, 5(8), R56.