Mechanisms of nucleosome dynamics in epigenetic inheritance

The National Institute of General Medical Sciences awarded the Regents of the University of Minnesota $386,879 on May 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the mechanisms governing nucleosome dynamics and epigenetic inheritance during cell division.

The research examines how parental histones transfer to newly replicated DNA strands during DNA replication and how this transfer regulates replication fork recovery under stress conditions. The project employs the ESPAN technique (enrichment and sequencing of protein-associated nascent DNA) to map protein interactions with leading and lagging DNA strands, enabling precise interrogation of nucleosome dynamics during chromatin replication. The work tests the hypothesis that proper control of parental histone transfer safeguards chromatin state stability and that histone chaperones for both newly synthesized and parental histones must cooperate to maintain chromatin structure during replication. The research also investigates the role of iron-sulfur assembly pathways in regulating histone transfer.

Performance occurs in Austin, Minnesota. The period of performance runs from May 1, 2026, through February 28, 2031. The award is classified as a Project Grant under the assistance type designation.

Abstract

Stable transmission of chromatin states, which encode epigenetic information, is essential for preserving gene expression patterns and maintaining cell identity across generations. Despite its importance, the mechanisms ensuring the intact transmission of chromatin structure and histone modifications during cell division remain poorly understood. The PI's long-term goal is to elucidate the mechanisms governing epigenetic inheritance, with a primary focus on nucleosome dynamics. The specific objectives for this funding period are to: (1) determine the regulatory mechanisms governing parental histone transfer to newly replicated DNA strands during DNA replication; (2) investigate how parental histone transfer pathways influence replication fork recovery under replication stress; and (3) examine the DNA replication strand preference of chaperones for newly synthesized histone in epigenetic inheritance. His central hypothesis is that proper control of parental histone transfer safeguards the stability of chromatin status inheritance, and that the transfer process is highly regulated by a variety of mechanisms, including the iron-sulfur assembly pathway. In addition, he hypothesizes that the chaperones for newly synthesized and parental histone must cooperate to maintain chromatin state during replication. The proposed work leverages innovative methodologies, including advancements in the espan technique (enrichment and sequencing of protein-associated nascent DNA). This technique, central to the project, enables precise mapping of protein interactions with the leading or lagging strands of replicating DNA. This technology allows researchers to interrogate the mechanisms regulating nucleosome dynamics during chromatin replication, an area that was previously difficult to study due to technical challenges. The outcome of this work will be elucidation of the regulatory mechanisms responsible for the transfer of parental histone H3-H4 tetramers and a better understanding of the importance of this process in chromatin stability. Aberrant regulation of proteins involved in chromatin replication, including histone chaperones, histone modification enzymes, and chromatin remodeling complexes, have been directly linked to breast, gastrointestinal, and prostate cancers. Thus, the mechanisms the PI uncovers for DNA replication-coupled histone transfer and assembly will not only provide new insights into the fundamental process of epigenetic inheritance, but also create new potential targets for human cancer therapies.