One of the central problems of biological sciences is to understand the manner in which the single-celled fertilized egg (the zygote) develops into a multicellular organism with a vast range of different cell types, each of which forms at the appropriate time and place relative to other cells. As will be discussed in this chapter, the regulation of gene transcription by specific transcription factors plays a key role in this process. A number of these transcription factors are expressed at specific times and places during embryonic development and play a central role in this process. Such regulation of transcription factor synthesis contrasts with the regulation of transcription factor activity that occurs in response to cellular signaling pathways, as discussed in the previous chapter.
Multiple-choice questions
Questions for Discussion
- More than 40% of the human genome consists of mobile pieces of DNA known as transposable elements. These elements have a propensity to insert randomly throughout the genome, but they are remarkably rare in the four gene clusters of homeobox genes, HoxA, HoxB, HoxC, and HoxD. Discuss the function of the Hox gene clusters in human development. Then, explain why transposable elements are rare in Hox gene clusters.
- Embryonic stem cells are maintained in an undifferentiated state by the transcription regulators Oct4, Sox2, and Nanog. The expression level of Oct4 is critical for stem cell differentiation. Normal levels of Oct4 maintain the undifferentiated state, but even a minor increase of 1.5-fold leads to mesoderm differentiation. Explain how a small change in Oct4 expression level can have a significant impact on the differentiation state of stem cells?
- Oct4 and Sox2 promote transcription of the FGF4 gene during embryogenesis, and a DNA element located at the 3′ end of the FGF4 gene is essential for their activity. This DNA element contains binding sites for Oct4 and Sox2 that are separated by three nucleotides. Scientists found that increasing the spacing between these binding sites by three or more nucleotides prevented Oct4 and Sox2 from promoting FGF4 transcription. Explore the function of FGF4 in embryonic development and elucidate why altering the distance between the Oct4 and Sox2 binding sites hindered the activation of FGF4 transcription.
- In embryogenesis, self-organized signaling is utilized to regulate gene expression and produce pattern formation. Discuss various mechanisms with specific examples by which self-organized signaling is achieved during development.
- Discuss various mechanisms that establish protein and mRNA gradients during oocyte maturation and asymmetric cell division.
Further Reading
Introduction
Vastenhouw, N. L., Cao, W. X., & Lipshitz, H. D. (2019). The maternal-to-zygotic transition revisited. Development (Cambridge, England), 146(11), dev161471. https://doi.org/10.1242/dev.161471
11.1 Regulation of gene expression in pluripotent embryonic stem cells
Aich, M., & Chakraborty, D. (2020). Role of lncRNAs in stem cell maintenance and differentiation. Current Topics in Developmental Biology, 138, 73–112. https://doi.org/10.1016/bs.ctdb.2019.11.003
Arabacı, D. H., Terzioğlu, G., Bayırbaşı, B., & Önder, T. T. (2021). Going up the hill: Chromatin-based barriers to epigenetic reprogramming. The FEBS Journal, 288(16), 4798–4811. https://doi.org/10.1111/febs.15628
Blanco, E., González-Ramírez, M., Alcaine-Colet, A., Aranda, S., & Di Croce, L. (2020). The Bivalent Genome: Characterization, Structure, and Regulation. Trends in Genetics: TIG, 36(2), 118–131. https://doi.org/10.1016/j.tig.2019.11.004
Fiorenzano, A., Pascale, E., Patriarca, E. J., Minchiotti, G., & Fico, A. (2019). LncRNAs and PRC2: Coupled Partners in Embryonic Stem Cells. Epigenomes, 3(3), 14. https://doi.org/10.3390/epigenomes3030014
Klein, D. C., & Hainer, S. J. (2020). Chromatin regulation and dynamics in stem cells. Current Topics in Developmental Biology, 138, 1–71. https://doi.org/10.1016/bs.ctdb.2019.11.002
Liu, L., & Warmflash, A. (2021). Self-organized signaling in stem cell models of embryos. Stem Cell Reports, 16(5), 1065–1077. https://doi.org/10.1016/j.stemcr.2021.03.020
Loh, C. H., & Veenstra, G. J. C. (2022). The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development. Epigenomes, 6(3), 23. https://doi.org/10.3390/epigenomes6030023
Macrae, T. A., Fothergill-Robinson, J., & Ramalho-Santos, M. (2023). Regulation, functions and transmission of bivalent chromatin during mammalian development. Nature Reviews. Molecular Cell Biology, 24(1), 6–26. https://doi.org/10.1038/s41580-022-00518-2
Pachano, T., Crispatzu, G., & Rada-Iglesias, A. (2019). Polycomb proteins as organizers of 3D genome architecture in embryonic stem cells. Briefings in Functional Genomics, 18(6), 358–366. https://doi.org/10.1093/bfgp/elz022
Park, J. W., Fu, S., Huang, B., & Xu, R.-H. (2020). Alternative splicing in mesenchymal stem cell differentiation. Stem Cells (Dayton, Ohio), 38(10), 1229–1240. https://doi.org/10.1002/stem.3248
Pascale, E., Caiazza, C., Paladino, M., Parisi, S., Passaro, F., & Caiazzo, M. (2022). MicroRNA Roles in Cell Reprogramming Mechanisms. Cells, 11(6), 940. https://doi.org/10.3390/cells11060940
Schulz, K. N., & Harrison, M. M. (2019). Mechanisms regulating zygotic genome activation. Nature Reviews. Genetics, 20(4), 221–234. https://doi.org/10.1038/s41576-018-0087-x
Verneri, P., Vazquez Echegaray, C., Oses, C., Stortz, M., Guberman, A., & Levi, V. (2020). Dynamical reorganization of the pluripotency transcription factors Oct4 and Sox2 during early differentiation of embryonic stem cells. Scientific Reports, 10(1), 5195. https://doi.org/10.1038/s41598-020-62235-0
Zaret, K. S. (2020). Pioneer Transcription Factors Initiating Gene Network Changes. Annual Review of Genetics, 54, 367–385. https://doi.org/10.1146/annurev-genet-030220-015007
11.2 Role of gene regulation in the development of Drosophila melanogaster
Mayr, C. (2019). What Are 3’ UTRs Doing? Cold Spring Harbor Perspectives in Biology, 11(10), a034728. https://doi.org/10.1101/cshperspect.a034728
Paul, R., Peraldi, R., & Kmita, M. (2024). The pioneering function of the hox transcription factors. Seminars in Cell & Developmental Biology, 152–153, 85–92. https://doi.org/10.1016/j.semcdb.2022.11.013
Saunders, T. E. (2021). The early Drosophila embryo as a model system for quantitative biology. Cells & Development, 168, 203722. https://doi.org/10.1016/j.cdev.2021.203722
Simsek, M. F., & Özbudak, E. M. (2022). Patterning principles of morphogen gradients. Open Biology, 12(10), 220224. https://doi.org/10.1098/rsob.220224
Wanninger, A. (2024). Hox, homology, and parsimony: An organismal perspective. Seminars in Cell & Developmental Biology, 152–153, 16–23. https://doi.org/10.1016/j.semcdb.2023.01.007
11.3 Role of homeodomain factors in mammalian development
Douceau, S., Deutsch Guerrero, T., & Ferent, J. (2023). Establishing Hedgehog Gradients during Neural Development. Cells, 12(2), 225. https://doi.org/10.3390/cells12020225
Ghyselinck, N. B., & Duester, G. (2019). Retinoic acid signaling pathways. Development, 146(13), dev167502. https://doi.org/10.1242/dev.167502
Miller, A., & Dasen, J. S. (2024). Establishing and maintaining Hox profiles during spinal cord development. Seminars in Cell & Developmental Biology, 152–153, 44–57. https://doi.org/10.1016/j.semcdb.2023.03.014
Płusa, B., & Piliszek, A. (2020). Common principles of early mammalian embryo self-organisation. Development, 147(14), dev183079. https://doi.org/10.1242/dev.183079
Ramírez-Colmenero, A., Oktaba, K., & Fernandez-Valverde, S. L. (2020). Evolution of Genome-Organizing Long Non-coding RNAs in Metazoans. Frontiers in Genetics, 11. https://doi.org/10.3389/fgene.2020.589697
Sagner, A., & Briscoe, J. (2019). Establishing neuronal diversity in the spinal cord: A time and a place. Development, 146(22), dev182154. https://doi.org/10.1242/dev.182154
Salomone, J., Farrow, E., & Gebelein, B. (2024). Homeodomain complex formation and biomolecular condensates in Hox gene regulation. Seminars in Cell & Developmental Biology, 152–153, 93–100. https://doi.org/10.1016/j.semcdb.2022.11.016