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bioRxiv · 10.1101/2025.09.09.672651

Non-centromeric CENP-A epigenetically regulates epithelial-mesenchymal plasticity and heterogeneity in human cells

Renaud-Pageot, C.·Capocefalo, D.·Lemaire, S.·Forest, A.·Cantini, L.·Almouzni, G.
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Abstract

The centromeric histone variant CENP-A, highly expressed in aggressive cancers, can promote an epithelial-mesenchymal transition (EMT) whose underlying mechanisms remain to decipher. Here, we tracked both the temporal dynamics of EMT states and CENP-A localization over time using a reversible high CENP-A expression system in human cells. Cell populations presenting hybrid EMT states at start, when exposed to high CENP-A levels, progressively accumulated mesenchymal states and displayed increased centromeric and ectopic CENP-A incorporation. Mechanistically, we reveal ectopic CENP-A gains at EMT genes by chromatin immunoprecipitation and identify two distinct EMT programs activated at different stages of the cell cycle by single-nucleus multi-omics. Importantly, while a pre-existent inflammatory program got amplified, high CENP-A induced a new developmental program. Remarkably, interrupting high CENP-A provision erased induced programs along with ectopic CENP-A incorporation, in line with non-genetic alterations. Our findings uncover an unconventional, non-centromeric function for CENP-A in epigenetically modulating epithelial-mesenchymal plasticity.

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Renaud-Pageot, C., Capocefalo, D., Lemaire, S., Forest, A., Cantini, L., Almouzni, G.. 2025-09-10. Non-centromeric CENP-A epigenetically regulates epithelial-mesenchymal plasticity and heterogeneity in human cells. https://doi.org/10.1101/2025.09.09.672651

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