Researchers from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) reported a parental histones inheritance safeguard mechanism in which parental histone allocation contributes to establishing chromatin states during cell differentiation through altering embryonic stem cell differentiation potential. 

The study was published in Nature Genetics on Sept. 4. 

The process of faithfully transferring and restoring histone posttranslational modifications based on parental histone allocation is central to maintaining cellular identity through cell division. 

Recent studies have revealed that replisome proteins Mcm2 and Pole3/Pole4 facilitate parental histone transfer to the replication lagging and leading strand. Whether parental histone allocation is regulated to allow programmed gene expression changes during cellular differentiation is still largely unknown. 

To explore the potential role of parental histone allocation in the process of cell differentiation, the researchers perturbed the symmetric parental histone posttranslational modification inheritance in mouse embryonic stem cells. They found that asymmetric parental histone inheritance alters H3K27me3 landscapes. The mutant cells could not fully differentiate along the neural lineage and mouse embryonic development. 

Combining single-cell transcriptomics and epigenomics with lineage tracing of cells, they showed that asymmetric parental histone inheritance up-regulates epigenetic and transcriptomic heterogeneity, alters H3.3 landscapes. The impaired neural differentiation was caused by a global redistribution of histone posttranslational modifications, especially H3K27me3, which altered the activation of neural lineage genes.  

This study demonstrates a direct link between DNA replication–coupled histone allocation and cell differentiation. 

Pablo Navarro, from Université Paris Cité, comment as follows: While the last couple of decades have been particularly fruitful regarding the molecular mechanisms associated with the maintenance of chromatin states during DNA replication, a major question had not yet been addressed: to what extent is the inheritance of histone modifications during DNA replication important to control cell identity? In a paper published in the new issue of Nature Genetics, the Gan lab experimentally assesses this key question, which stands at the heart of the field of Epigenetics. This study rich the conclusions: the epigenetic inheritance of histone modifications is involved in the proper establishment of new cell identities, demonstrating that epigenetic control is not a mere mechanism stabilizing established cell states. Rather, it strongly contributes to the dynamic changes of cell fate required for development.

Media Contact:
ZHANG Xiaomin
Email:xm.zhang@siat.ac.cn