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Horizontal Transfer of Histone H3 by Mammalian Cells

By Parker L. Sulkowski, Hilary E. Nicholson, Matthew Z. Li, Norbert Perrimon, Zhe Liu, William G. Kaelin

Posted 30 Jun 2021
bioRxiv DOI: 10.1101/2021.06.30.450524

Histones are small, highly basic, nuclear proteins that serve as structural elements to condense DNA into chromatin and regulate its accessibility1. Although histones released from dying cells can act as extracellular signaling molecules, all intracellular histone molecules are assumed to have originated from the cell in which they reside2-6. Here we show that histone H3 is horizontally transferred between viable cells. Using an ER-targeted biotin ligase to detect secreted proteins7,8, we serendipitously discovered that histone H3 is selectively secreted by autophagic cells relative to histones H2A, H2B, and H4. Specific H3 posttranslational modifications are enriched or depleted on secreted H3 relative to intracellular H3, suggesting that specific PTMs dictate H3's ability to be secreted or the information it conveys to neighboring cells. Remarkably, we found that secreted H3 can enter the nuclei of recipient cells in an autophagy-independent and cell contact-independent manner ex vivo and in vivo. These findings have implications for cell-cell communication during nutrient deprivation, hypoxia, and perhaps other forms of cellular stress, and for the ability to deliver macromolecules across cell membranes.

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