Identification of epigenetic modulators as determinants of nuclear size and shape
The shape and size of the human cell nucleus is highly variable amongst cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters and eliminating cell cycle effectors, we identified a set of novel determinants of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Finally, oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.
All data generated are included in the manuscript.
Article and author information
National Institutes of Health (NIH 1-ZIA-BC010309-23)
- Tom Misteli
National Institutes of Health (NIH 1-ZIC-BC011567-08)
- Gianluca Pegoraro
National Institutes of Health (NIH R35GM134885)
- Daniel L Levy
National Institutes of Health (NIH P20GM103432)
- Daniel L Levy
USDA National Institute of Food and Agriculture (Hatch project #1012152)
- Daniel L Levy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Megan C King, Yale School of Medicine, United States
- Received: May 29, 2022
- Accepted: May 4, 2023
- Accepted Manuscript published: May 23, 2023 (version 1)
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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