Faithful inheritance of parental histones is essential to maintain epigenetic information and cellular identity during cell division. Parental histones are evenly deposited onto the replicating DNA of sister chromatids in a process dependent on the MCM2 subunit of DNA helicase. However, the impact of aberrant parental histone partition on human disease such as cancer is largely unknown. In this study, we construct a model of impaired histone inheritance by introducing MCM2-2A mutation (defective in parental histone binding) in MCF-7 breast cancer cells. The resulting impaired histone inheritance reprograms the histone modification landscapes of progeny cells, especially the repressive histone mark H3K27me3. Lower H3K27me3 levels derepress the expression of genes associated with development, cell proliferation, and epithelial to mesenchymal transition. These epigenetic changes confer fitness advantages to some newly emerged subclones and consequently promote tumor growth and metastasis after orthotopic implantation. In summary, our results indicate that impaired inheritance of parental histones can drive tumor progression.
Bibliographical noteFunding Information:
This work was supported by the following fundings: National Key R&D Program of China (Grant No. 2019YFA0903800 to H.G.), the Major Program of the National Natural Science Foundation of China (32090031 to H.G.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0480000 to H.G.), the General Program of the National Natural Science Foundation of China (32070610 to H.G.), the National Natural Science Foundation of China for Young Scholars (32000580 to Q.W., 32100460 to J.Z. and 32101178 to Y.Y.), the Guangdong Province Fund for Distinguished Young Scholars (2021B1515020109 to H.G.), Guangdong Basic and Applied Basic Research Foundation (2021A1515110377 to X.K.), Shenzhen Institute of Synthetic Biology Scientific Research Program (JCHZ20200005, DWKF20210001, ZTXM20190019 to H.G.), and Project funded by China Postdoctoral Science Foundation (2021M693301 to C.T and 2021M703386 to J.Z.).
© 2023, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't