Epigenetics involves all mechanisms of biological inheritance that do not include changes in DNA sequence. It has been implicated in regular developmental processes like cell differentiation, as well as in pathological processes like cancers and psychological disorders. One of the major mechanisms of epigenetic inheritance is through histone modifications. Histones are proteins responsible for tight packing of DNA into small units called nucleosomes. Histone tails extend beyond nucleosomes and they are susceptible to certain modifications that represent epigenetic marks. In turn, these marks signal whether a gene where they are located is going to be expressed or not. Therefore, it is of utmost importance that epigenetic marks are maintained during DNA replication. As replication machinery proceeds along DNA, it needs to disassemble tightly packed histone-DNA units (nucleosomes) in order to access DNA and duplicate it. These histones in front of the replication machinery are called parental histones. However, replication machinery also needs to keep disassembled parental histones with their particular epigenetic marks close by, and to hand them over to two newly duplicated DNA (labelled as leading and lagging strand) where they are subsequently assembled into new nucleosomes. In this way, two duplicated DNA molecules will keep the same epigenetic marks as the original DNA molecule.
The main objective of this project is to unravel how replication machinery disassembles nucleosome, how it keeps parental histones close by and how it hands them over to two newly duplicated DNA strands. Epigenetic inheritance is of significant importance for wider society, as it is involved in widespread medical conditions like behavioural disorders, cancers, diabetes and heart problems, as well as in ageing. Understanding molecular mechanism of epigenetic inheritance is required for development of epigenetic therapies that have already shown potential in treatments of certain cancers.
This project has shed some valuable light on the previously unknown mechanism of parental histone recycling. It identified key components of the replication machinery that are responsible for keeping parental histones by its side and offered clues for understanding how they are subsequently handed over behind the replication machinery, towards new DNA strands.
