To keep cell identity, chromatin states and the epigenetic data they are associated with must be faithfully passed down through cellular divisions. Numerous disorders, including cancer, are linked to epigenetic irregularities. Histone post-translational modifications (PTMs), which are significant regulators of gene transcription and determinants of cellular epigenetic status, convey epigenetic data.
Chromatin states and epigenetic information are critical for cell identity and gene transcription regulation. Histone post-translational modifications (PTMs) are important in cellular epigenetic states because they carry epigenetic information and regulate gene transcription.
A team from the Chinese Academy of Sciences Shenzhen Institute of Advanced Technology (SIAT) developed a tumor model that introduces an MCM2-2A mutation, which is defective in parental histone binding, into breast cancer cell lines to investigate the impact of impaired parental histone inheritance on histone modification profiles in MCM2 mutant cells.
Impaired paternal histone inheritance has been associated with various illnesses, including cancer. According to a Shenzhen Institute of Advanced Technology (SIAT) study, defective parental histone inheritance resulted in considerable epigenetic reprogramming, specifically impacting the restrictive histone mark H3K27me3.Â
Prof GAN Yunhai, corresponding author of the study, “The loss of H3K27me3 at the promoters of development-related genes resulted in their activation in cancer cells, thereby promoting tumor growth and metastasis.”Â
Furthermore, after orthotopic transplantation, cancer cells with defective histone inheritance showed faster proliferation and a proclivity to become more aggressive.
Single-cell RNA sequencing study later demonstrated that newly produced subclones in cancer cells with abnormal histone inheritance aided tumor development. These subclones gained fitness and proliferation advantages, growing more quickly in environments with greater complexity.
Cancer cells with faulty histone inheritance grew faster and were more aggressive following orthotopic transplantation. Subclones in cancer cells with histone inheritance abnormalities aided tumor growth by gaining a competitive advantage in proliferation and fitness.
This study confirms the importance of parental histone inheritance carrying H3K27me3 in maintaining specific areas of differentiated cells. Failure to repair H3K27me3 can reactivate mammary gland growth processes, frequently used as tumor progression drivers by breast cancer cells. By conserving epigenetic stability, targeting aberrant epigenetic inheritance may enhance patient outcomes.
The researcher said, “These findings provide valuable insights into how epigenetic instability contributes to tumor progression, suggesting that targeting abnormal epigenetic inheritance may improve patient outcomes by preserving epigenetic stability.”Â
Journal Reference:
- Tian, C., Zhou, J., Li, X. et al. Impaired histone inheritance promotes tumor progression. Nature Communication. DOI:10.1038/s41467-023-39185-y