Transmission of Epigenetic Information through Histone Proteins at Replication Forks

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The term 'epigenetics' refers to changes on chromatin that alter gene expression. Unlike the genetic information encoded in DNA proper, environmental factors further influence and diversify the epigenetic landscape of cells. Importantly, these changes to chromatin can be inherited through cell division and perpetuate phenotypes from mother to daughter cells.* My research program focuses on how mammalian cells inherit and maintain epigenetic information as they divide. I am particularly interested in histone proteins, which fold and organize DNA into nucleosomes and, ultimately, chromatin fibres. Histones are heavily modified by a gamut of enzymes. These modifications have a direct impact on chromatin structure and gene expression, and can be inherited to influence gene activity through numerous cell divisions. My long-term goals are to identify the cellular mechanisms by which epigenetic information found on histones is transmitted as cells divide. This includes the transmission and propagation of histones proper, the epigenetic marks that they carry, and the histone-binding proteins that affect chromatin structures and gene expression. The immediate goals of this proposal are to determine how histones carrying epigenetic information segregate as they encounter the replication fork.* The work proposed herein uses two novel biochemical assays that I have developed: the first will allow me to isolate factors that allow the replicative helicase to unwind nucleosomal DNA; whereas the second measures histone eviction. Together, these assays will be used to identify the proteins that segregate histones at replication forks and which are needed to initiate the transmission of epigenetic information found on histones. The same assays will then be used to determine whether different factors are needed to transmit epigenetic information on 'open' euchromatin and 'repressed' heterochromatin in S-phase.* The results will advance our understanding of how cells maintain correct DNA organization as DNA duplicates. It touches on a fundamental, but vital question on cell function with direct implications in biotechnology and cell engineering.*