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Altered expression response upon repeated gene repression

Cells must continuously adjust to their environments and cope with changing temperatures, stress conditions, or resources. Particularly, if conditions change repeatedly, it might make sense for cells to adjust more effectively. A collaborative between researchers from the Institute for AI in Health and the Institute of Functional Epigenetics at Helmholtz Munich has shown that cells indeed show a faster gene-deactivating response upon repeated stimulation.

Early work had revealed that yeast cells activate the carbon source (sugar) -responsive gene, galactokinase 1 (Gal1), faster upon a repeat alternation of the carbon source. Whether the same gene is also faster deactivated has been less studied. However, to understand how cells regulate their genes, understanding both gene activation and deactivation is important.

Schuh et al. investigated the expression kinetics of Gal1 across repeated deactivations (repressions). They measured the single-cell protein expression of Gal1 in over 1,500 individual cells across repeated carbon source shifts and used mathematical modeling to evaluate potential causes underlying an observed faster repression response upon a second carbon source shift. They found that the faster response is mediated by a shortened repression response delay, the estimated time between carbon source shift, and Gal1 protein production termination[RS1] .

Collectively, this study provides a quantitative description of repression kinetics in single cells and allows to pinpoint potential mechanisms underlying an altered response upon repeated changes in sugar uptake, which is thought to contribute to diabetes progression in humans. Thus, the work lays the foundation for studying the transcriptional kinetics during for example insulin resistance and could contribute to the development of further diabetes therapies.

Further information:

This was a successful, interdisciplinary Helmholtz Munich collaboration. Lea Schuh, Melanie Schulz, Maria Bordukova, and Carsten Marr are part of the Institute of AI for Health. Lea Schuh, Igor Kukhtevich, Poonam Bheda, and Robert Schneider are part of the Institute of Functional Epigenetics.

Schuh L, Kukhtevich I, Bheda P, Schulz M, Bordukova M, et al. (2022) Altered expression response upon repeated gene repression in single yeast cells.PLOS Computational Biology 18(10): e1010640.