Restoring chromatin and epigenetics

Karim Labib's lab studies how the replisome contributes to the restoration of parental chromatin and the preservation of epigenetic information.

Chromatin is the substrate and also the product of chromosome duplication in eukaryotes.  Very little is known about how the CMG helicase is able to traverse chromatin, or about how chromatin is regenerated subsequently.  The unwinding of the DNA duplex will lead locally to displacement of parental histones, which must then be retained at the fork, if they are to be re-deposited onto the newly replicated DNA at the same locus, in order to preserve the epigenetic histone modifications that control gene expression.  It appears that a parental H3-H4 tetramer is retained at the fork and is then transferred to the newly replicated DNA as an intact unit.  This requires histone chaperones that are able to bind to tetrameric H3-H4, and we are exploring the idea that such chaperones are contained within the replisome itself.

 

Our former PhD student Magda Foltman identified a small motif in the amino terminal tail of Mcm2, which binds to parental histones and is important to preserve a repressive form of chromatin near telomeres (Foltman et al, Cell Rep., 2013).  Magda identified two key tyrosines in the Mcm2 tail that are critical for histone-binding activity, and subsequent crystal structures from the labs of Anja Groth and Genevieve Almouzni showed that these tyrosines make key contacts with residues of H3 and H4 that are exposed on the outside of an H3-H4 tetramer.  Cecile Evrin in our lab is now studying additional  replisome components that have histone chaperone activity.  We are also interested in the parallels between the histone processing machinery of the chromosome replication and transcriptional machineries (as they both share a very similar challenge to reproduce chromatin after unwinding of the parental DNA duplex).

 

Karim Labib's lab studies how the replisome contributes to the restoration of parental chromatin and the preservation of epigenetic information.
Karim's lab is located within the MRC PPU, which is part of the School of Life Sciences in the University of Dundee.
Karim Labib's lab studies how the replisome contributes to the restoration of parental chromatin and the preservation of epigenetic information.