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Published October 2021 | public
Journal Article

Nuclear compartmentalization as a mechanism of quantitative control of gene expression


Gene regulation requires the dynamic coordination of hundreds of regulatory factors at precise genomic and RNA targets. Although many regulatory factors have specific affinity for their nucleic acid targets, molecular diffusion and affinity models alone cannot explain many of the quantitative features of gene regulation in the nucleus. One emerging explanation for these quantitative properties is that DNA, RNA and proteins organize within precise, 3D compartments in the nucleus to concentrate groups of functionally related molecules. Recently, nucleic acids and proteins involved in many important nuclear processes have been shown to engage in cooperative interactions, which lead to the formation of condensates that partition the nucleus. In this Review, we discuss an emerging perspective of gene regulation, which moves away from classic models of stoichiometric interactions towards an understanding of how spatial compartmentalization can lead to non-stoichiometric molecular interactions and non-linear regulatory behaviours. We describe key mechanisms of nuclear compartment formation, including emerging roles for non-coding RNAs in facilitating their formation, and discuss the functional role of nuclear compartments in transcription regulation, co-transcriptional and post-transcriptional RNA processing, and higher-order chromatin regulation. More generally, we discuss how compartmentalization may explain important quantitative aspects of gene regulation.

Additional Information

© 2021 Nature Publishing Group. Accepted 28 May 2021; Published 02 August 2021. The authors thank members of the Guttman laboratory, especially M. Strehle, J. Jachowicz, S. Quinodoz and I. Goronzy for helpful comments and discussions, I.-M. Strazhnik for figures and S. Hiley for editing. P.B. is supported by the University of California, Los Angeles (UCLA)-Caltech Medical Scientist Training Program (MSTP), National Institutes of Health (NIH) F30CA247447 and a Chen Graduate Innovator Grant. M.G. is a New York Stem Cell Foundation Robertson Investigator and an investigator at the Heritage Medical Research Institute. Research in the Guttman laboratory is funded by the NIH 4DN programme, an NIH Director's Transformative R01 Award, the Chan-Zuckerberg Initiative and funds from Caltech. Author Contributions: The authors contributed equally to all aspects of the article. The authors declare no competing interests. Peer review information: Nature Reviews Molecular Cell Biology thanks Sergey Razin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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August 22, 2023
December 22, 2023