Tarbier, MarcelMackowiak, Sebastian D.Frade, JoãoCatuara Solarz, Silvina, 1986-Biryukova, InnaGelali, EleniBárcena Menéndez, Diego, 1984-Zapata Ortiz, Luis, 1985-Ossowski, StephanBienko, MagdaGallant, Caroline J.Friedländer, Marc R.2020-11-162020-11-162020Tarbier M, Mackowiak SD, Frade J, Catuara-Solarz S, Biryukova I, Gelali E, Menéndez DB, Zapata L, Ossowski S, Bienko M, Gallant CJ, Friedländer MR. Nuclear gene proximity and protein interactions shape transcript covariations in mammalian single cells. Nat Commun. 2020; 11(1):5445. DOI: 10.1038/s41467-020-19011-52041-1723http://hdl.handle.net/10230/45767Single-cell RNA sequencing studies on gene co-expression patterns could yield important regulatory and functional insights, but have so far been limited by the confounding effects of differentiation and cell cycle. We apply a tailored experimental design that eliminates these confounders, and report thousands of intrinsically covarying gene pairs in mouse embryonic stem cells. These covariations form a network with biological properties, outlining known and novel gene interactions. We provide the first evidence that miRNAs naturally induce transcriptome-wide covariations and compare the relative importance of nuclear organization, transcriptional and post-transcriptional regulation in defining covariations. We find that nuclear organization has the greatest impact, and that genes encoding for physically interacting proteins specifically tend to covary, suggesting importance for protein complex formation. Our results lend support to the concept of post-transcriptional RNA operons, but we further present evidence that nuclear proximity of genes may provide substantial functional regulation in mammalian single cells.application/pdfeng© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-020-19011-5Functional genomicsGene regulatory networksTranscriptomicsinfo:eu-repo/semantics/openAccess