Gene traits are the characteristics that are inherited from parents to offspring through DNA. They are influenced by epigenetics, which are molecular switches that can turn genes on or off without changing the DNA sequence. Epigenetics are affected by various environmental factors, such as nutrition, stress, lifestyle, and environmental exposures.
How are gene traits passed on during cell division? This is a fundamental question in biology that has puzzled scientists for decades. A research team has recently made a significant breakthrough in understanding how the DNA copying machine, called the replisome, helps pass on epigenetic information to maintain gene traits at each cell division. Understanding how this coupled mechanism works could lead to new treatments for cancer and other epigenetic diseases by targeting specific changes in gene activity. Their findings have recently been published in Nature.
The DNA copying machine and epigenetic information
In our cells, DNA is organized into chromatin, which consists of repeating units of DNA wrapped around proteins called histones. Each unit is called a nucleosome and carries epigenetic tags, also known as histone modifications, that regulate gene expression. During DNA replication, parental nucleosomes carrying the epigenetic tags are dismantled and recycled, ensuring the accurate transfer of epigenetic information to new cells during cell division. Errors in this process can alter the epigenetic landscape, gene expression and cell identity, with potential implications for cancer and aging.
Despite extensive research, the molecular mechanism by which epigenetic information is passed down through the replisome remains unclear. This knowledge gap is primarily due to the absence of detailed structures that capture the replisome in action when transferring parental histones with epigenetic tags. Studying the process is challenging because of the fast-paced nature of chromatin replication, as it involves rapid disruption and restoration of nucleosomes to keep up with the swift DNA synthesis.
A breakthrough discovery using cryo-EM
The research team used a cutting-edge technique called cryo-electron microscopy (cryo-EM) to visualize the structure of the yeast replisome in complex with a protein called FACT and parental histones. FACT is a key factor that facilitates chromatin replication by destabilizing and reassembling nucleosomes. The researchers captured snapshots of different stages of chromatin replication and revealed how FACT interacts with the replisome and parental histones to ensure their faithful inheritance.
The researchers found that FACT binds to both the replisome and parental histones simultaneously, forming a bridge that connects them. This bridge allows FACT to deliver parental histones directly to the newly synthesized DNA strand, where they are incorporated into new nucleosomes. The researchers also discovered that FACT has a preference for binding to H3-H4 tetramers over H2A-H2B dimers, which are two types of histone subunits that make up a nucleosome. This preference ensures that H3-H4 tetramers, which carry most of the epigenetic information, are preferentially recycled and passed on to new cells.
The researchers also showed that FACT can bind to different types of histone modifications, suggesting that it can recognize and preserve diverse epigenetic states during chromatin replication. Furthermore, they demonstrated that FACT can cooperate with another protein called MCM2-7 helicase, which unwinds the DNA ahead of the replisome, to facilitate nucleosome disassembly and assembly.
Implications for future research and applications
The research team has provided unprecedented insights into how the DNA copying machine helps pass on epigenetic information to maintain gene traits at each cell division. Their findings have advanced our understanding of the molecular basis of chromatin replication and epigenetic inheritance, which are fundamental processes in biology.
The findings also have implications for future research and applications in biotechnology and medicine. For example, by manipulating FACT or other factors involved in chromatin replication, it may be possible to alter or correct epigenetic states that are associated with diseases such as cancer or aging. Alternatively, by using FACT or other factors as tools, it may be possible to engineer or modify gene traits in cells or organisms for various purposes.
The research team hopes that their work will inspire further studies on chromatin replication and epigenetic inheritance in different organisms and systems, as well as on their roles in development, differentiation and disease.
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