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Transcription Factors and Splice Factors—Interconnected Regulators of Stem Cell Differentiation

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Abstract

Purpose of Review

The underlying molecular mechanisms that direct stem cell differentiation into fully functional, mature cells remain an area of ongoing investigation. Cell state is the product of the combinatorial effect of individual factors operating within a coordinated regulatory network. Here, we discuss the contribution of both gene regulatory and splicing regulatory networks in defining stem cell fate during differentiation and the critical role of protein isoforms in this process.

Recent Findings

We review recent experimental and computational approaches that characterize gene regulatory networks, splice regulatory networks, and the resulting transcriptome and proteome they mediate during differentiation. Such approaches include long-read RNA sequencing, which has demonstrated high-resolution profiling of mRNA isoforms, and Cas13-based CRISPR, which could make possible high-throughput isoform screening. Collectively, these developments enable system-level profiling of factors contributing to cell state.

Summary

Overall, gene and splice regulatory networks are important in defining cell state. The emerging high-throughput system-level approaches will characterize the gene regulatory network components necessary in driving stem cell differentiation.

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Acknowledgements

Current Stem Cell Reports is grateful to Editor in Chief, Graça Almeida-Porada, MD, PhD, for her review of this manuscript.

Funding

This study was funded by grants T32HL007284 to MMM and R35GM142647-02 to GMS. M. N. K.-M. is partly supported by the following grants: NIH/NHLBI 5R01HL157780-02, NIH/NHLBI 1R01HL150589-01A1, Additional Ventures Single Ventricle Research Fund 1048010, Additional Ventures Expansion Award 988513, and American Heart Association 20TPA35490206. C.L.M. is supported by the following grants: NIH/NHLBI R01HL148239, NIH/NHLBI R01HL164577, and Fondation Leducq “PlaqOmics” 18CVD02.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22903, USA

    Madison M. Mehlferber

  2. Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine Fontaine Medical Office Building 1, 418 Ray C Hunt Dr., Charlottesville, VA, 22903, USA

    Muge Kuyumcu-Martinez

  3. Department of Public Health Sciences, Department of Biochemistry and Molecular Genetics, and Department of Biomedical Engineering, University of Virginia, Multistory Building, West Complex, 1335 Lee St, Charlottesville, VA, 22908, USA

    Clint L. Miller

  4. Department of Molecular Physiology and Biological Physics, Center for Public Health Genomics, UVA Comprehensive Cancer Center, Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA, 22903, USA

    Gloria M. Sheynkman

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Correspondence to Gloria M. Sheynkman.

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Madison M. Mehlferber, Muge Kuyumcu, Gloria M. Sheynkman declare they have no conflict of interest. Clint L. Miller has received funding support from AstraZeneca for work unrelated to the current study.

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Mehlferber, M.M., Kuyumcu-Martinez, M., Miller, C.L. et al. Transcription Factors and Splice Factors—Interconnected Regulators of Stem Cell Differentiation. Curr Stem Cell Rep 9, 31–41 (2023). https://doi.org/10.1007/s40778-023-00227-2

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