Whitcomb SJ, Fierz B, McGinty RK, Holt M, Ito T, Muir TW, Allis CD

It is well established that chromatin is a destination for signal transduction affecting many DNA-templated processes. Histone proteins in particular are extensively post- translationally modified. We are interested in how the complex repertoire of histone modifications is coordinately regulated to generate meaningful combinations of ″marks″ at physiologically relevant genomic locations. ...

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One important mechanism is ″crosstalk″ between pre-existing histone post-translational modifications (PTMs) and enzymes that subsequently add or remove modifications on chromatin. Here, we use chemically-defined ″designer″ nucleosomes to investigate novel enzymatic crosstalk relationships between the most abundant histone ubiquitylation sites, H2AK119ub and H2BK120ub, and two important histone methyltransferases, Disruptor of Telomeric Silencing 1-Like (Dot1L) and Polycomb Repressive Complex 2 (PRC2). While the presence of H2Bub in nucleosomes greatly stimulates Dot1L methylation of histone H3 lysine 79 (H3K79), we find that H2Aub does not influence Dot1L activity. In contrast, we show that H2Aub inhibits PRC2 methylation of histone H3 lysine 27 (H3K27), but H2Bub does not influence PRC2 activity. Taken together, these results highlight how the position of nucleosome monoubiquitylation affects the specificity and direction of crosstalk with enzymatic activities on chromatin.

Date: May. 22, 2012

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