Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar;14(2):e1752.
doi: 10.1002/wrna.1752. Epub 2022 Jul 28.

Integrating transcription and splicing into cell fate: Transcription factors on the block

Panagiotis Boumpas  1 , Samir Merabet  1 , Julie Carnesecchi  1
Affiliations
Review

Integrating transcription and splicing into cell fate: Transcription factors on the block

Panagiotis Boumpas et al. Wiley Interdiscip Rev RNA. 2023 Mar.

Abstract

Transcription factors (TFs) are present in all life forms and conserved across great evolutionary distances in eukaryotes. From yeast to complex multicellular organisms, they are pivotal players of cell fate decision by orchestrating gene expression at diverse molecular layers. Notably, TFs fine-tune gene expression by coordinating RNA fate at both the expression and splicing levels. They regulate alternative splicing, an essential mechanism for cell plasticity, allowing the production of many mRNA and protein isoforms in precise cell and tissue contexts. Despite this apparent role in splicing, how TFs integrate transcription and splicing to ultimately orchestrate diverse cell functions and cell fate decisions remains puzzling. We depict substantial studies in various model organisms underlining the key role of TFs in alternative splicing for promoting tissue-specific functions and cell fate. Furthermore, we emphasize recent advances describing the molecular link between the transcriptional and splicing activities of TFs. As TFs can bind both DNA and/or RNA to regulate transcription and splicing, we further discuss their flexibility and compatibility for DNA and RNA substrates. Finally, we propose several models integrating transcription and splicing activities of TFs in the coordination and diversification of cell and tissue identities. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Splicing Mechanisms.

Keywords: alternative splicing; cell fate; gene regulation; transcription; transcription factor.

PubMed Disclaimer

References

FURTHER READING
Methods
    1. Drexler, H. L., Choquet, K., Merens, H. E., Tang, P. S., Simpson, J. T., & Churchman, L. S. (2021). Revealing nascent RNA processing dynamics with nano-COP. Nature Protocols, 16(3), 1343-1375. https://doi.org/10.1038/s41596-020-00469-y
    1. Ibrahim, F., Oppelt, J., Maragkakis, M., & Mourelatos, Z. (2021). TERA-Seq: True end-to-end sequencing of native RNA molecules for transcriptome characterization. Nucleic Acids Research, 49(20), e115. https://doi.org/10.1093/nar/gkab713
Pol II cluster in vivo
    1. Pancholi, A., Klingberg, T., Zhang, W., Prizak, R., Mamontova, I., Noa, A., Sobucki, M., Kobitski, A. Y., Nienhaus, G. U., Zaburdaev, V., & Hilbert, L. (2021). RNA polymerase II clusters form in line with surface condensation on regulatory chromatin. Molecular Systems Biology, 17(9), e10272. https://doi.org/10.15252/msb.202110272
Linking transcriptome and translatome
    1. Tress, M. L., Abascal, F., & Valencia, A. (2017). Alternative splicing May not be the key to proteome complexity. Trends in Biochemical Sciences, 42(2), 98-110. https://doi.org/10.1016/j.tibs.2016.08.008
    1. Wang, Z.-Y., Leushkin, E., Liechti, A., Ovchinnikova, S., Mößinger, K., Brüning, T., Rummel, C., Grützner, F., Cardoso-Moreira, M., Janich, P., Gatfield, D., Diagouraga, B., de Massy, B., Gill, M. E., Peters, A. H. F. M., Anders, S., & Kaessmann, H. (2020). Transcriptome and translatome co-evolution in mammals. Nature, 588(7839), 642-647. https://doi.org/10.1038/s41586-020-2899-z
Splicing and evolution
    1. Baeza-Centurion, P., Miñana, B., Schmiedel, J. M., Valcárcel, J., & Lehner, B. (2019). Combinatorial genetics reveals a scaling law for the effects of mutations on splicing. Cell, 176(3), 549-563.e23. https://doi.org/10.1016/j.cell.2018.12.010
    1. Barbosa-Morais, N. L., Irimia, M., Pan, Q., Xiong, H. Y., Gueroussov, S., Lee, L. J., Slobodeniuc, V., Kutter, C., Watt, S., Çolak, R., Kim, T., Misquitta-Ali, C. M., Wilson, M. D., Kim, P. M., Odom, D. T., Frey, B. J., & Blencowe, B. J. (2012). The evolutionary landscape of alternative splicing in vertebrate species. Science, 338(6114), 1587-1593. https://doi.org/10.1126/science.1230612
    1. Fiszbein, A., Krick, K. S., Begg, B. E., & Burge, C. B. (2019). Exon-mediated activation of transcription starts. Cell, 179(7), 1551-1565.e17. https://doi.org/10.1016/j.cell.2019.11.002
REFERENCES
    1. Aebi, M., Hornig, H., Padgett, R. A., Reiser, J., & Weissmann, C. (1986). Sequence requirements for splicing of higher eukaryotic nuclear pre-mRNA. Cell, 47(4), 555-565. https://doi.org/10.1016/0092-8674(86)90620-3
    1. Agirre, E., Oldfield, A. J., Bellora, N., Segelle, A., & Luco, R. F. (2021). Splicing-associated chromatin signatures: A combinatorial and position-dependent role for histone marks in splicing definition. Nature Communications, 12(1), 682. https://doi.org/10.1038/s41467-021-20979-x
    1. Aiyar, S. E., Sun, J., Blair, A. L., Moskaluk, C. A., Lu, Y., Ye, Q., Yamaguchi, Y., Mukherjee, A., Ren, D., Handa, H., & Li, R. (2004). Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes & Development, 18(17), 2134-2146. https://doi.org/10.1101/gad.1214104
    1. Alharbi, A. B., Schmitz, U., Marshall, A. D., Vanichkina, D., Nagarajah, R., Vellozzi, M., Wong, J. J., Bailey, C. G., & Rasko, J. E. (2021). Ctcf haploinsufficiency mediates intron retention in a tissue-specific manner. RNA Biology, 18(1), 93-103. https://doi.org/10.1080/15476286.2020.1796052
    1. Ameur, A., Zaghlool, A., Halvardson, J., Wetterbom, A., Gyllensten, U., Cavelier, L., & Feuk, L. (2011). Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain. Nature Structural & Molecular Biology, 18(12), 1435-1440. https://doi.org/10.1038/nsmb.2143

Publication types

LinkOut - more resources