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bioRxiv · 10.1101/2024.07.17.603871

Multimodal screen reveals noise regulatory proteins

Garcia-Blay, O.·Hu, X.·Wassermann, C. L.·van Bokhoven, T.·Struijs, F. M. B.·Hansen, M. M. K.
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Abstract

Gene-expression noise can influence cell-fate choices across pathology and physiology. However, a crucial question persists: do regulatory proteins or pathways exist that control noise independently of mean expression levels? Our integrative approach, combining single-cell RNA sequencing with proteomics and regulator enrichment analysis, reveals 32 putative noise regulators. SON, a nuclear speckle-associated protein, alters transcriptional noise without changing mean expression levels. Furthermore, SONs noise regulation can propagate to the protein level. Long-read and total RNA sequencing shows that SONs noise regulation does not significantly change isoform usage or splicing efficiency. Moreover, SON depletion reduces state-switching in pluripotent mouse embryonic stem cells and impacts their fate choice during differentiation. Collectively, we discover a class of proteins that regulates noise orthogonally to mean expression levels. This work serves as a proof-of-concept that can identify other functional noise-regulators throughout development and disease progression.

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Garcia-Blay, O., Hu, X., Wassermann, C. L., van Bokhoven, T., Struijs, F. M. B., Hansen, M. M. K.. 2024-07-21. Multimodal screen reveals noise regulatory proteins. https://doi.org/10.1101/2024.07.17.603871

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