Not so long ago, the role of chromatin in DNA regulation was assumed to be passive. Text books spoke of the role of nucleosomes as DNA compressors – allowing the massive amount of DNA to be fitted neatly into the vanishingly small nucleus. The work of Wolffe, Workman, Allis, Felsenfeld and many others showed that, far from being passive, chromatin played a very active role in nuclear organization. In many case, chromatin is instrumental in the fundamental process of transcriptional regulation, replication and cell cycling. Many of these active roles for chromatin are mediated by molecular modifications of the histone tails. These include acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation. These telltales, or signposts, serve to recruit other cofactors as well as to modify the properties of the underlying nucleosome.
In a landmark paper published in Nature this week, Allis and colleagues show a mechanism for the regulation of HP1 binding. HP1 is, in part, responsible for the formation of heterochromatin and, as such, is repressive. During early mitosis the chromatin must become 'looser' to allow the replication machinery access to those chromatic strands repressed in refractory herterochromatin and so HP1 release is vital for appropriate mitotic cycling. The process governing HP1 release is now elucidated.
HP1 binding to heterochromatin is mediated by a trimethylation of Histone H3 Lysine 9. This modification recruits HP1 though the binding is weak. Allis et al., have found that phosphorylation of the adjacent Serine 10 completely abolishes HP1 interaction and is responsible for the removal of HP1 during mitosis. This phosphorylation is mediated by the aurora B kinase and the work shows that inhibition of this enzyme abolishes the loss of HP1. These data, then suggest a central role for HP1, and consequently for the dual markers of Histone H3, in the mediation of cell cycle control.
This work clearly demonstrates another level of complexity in epigenetic regulation and further highlights the active role of chromatin in the fundamental processes of the nucleus
Message posted by: Simon Chandler
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