Abstract
The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001.
Highlights
An orchestra of chromatin readers, writers, and erasers act on diverse covalent histone modifications to establish particular cell fates (Rando and Chang, 2009)
WDR5 is important for mammalian embryonic stem cell (ESC) self renewal and maintenance of active chromatin for pluripotency genes, and WDR5 is required for efficient generation of induced pluripotent stem cells from differentiated somatic cells (Ang et al, 2011; Li et al, 2012)
The MLL and H3R2me2s share the same binding pocket, and we found that HOTTIP and RbBP5 share a distinct binding pocket
Summary
An orchestra of chromatin readers, writers, and erasers act on diverse covalent histone modifications to establish particular cell fates (Rando and Chang, 2009). By maintaining such histone modifications through cell divisions, the cell state can be epigenetically transferred from generation to generation, eventually establishing tissues and complex organisms. Of the various cofactors that regulate MLL activity, WDR5 is a important multifunctional adaptor protein that can discriminate posttranslational modifications on histone tails, as well as bind to the MLL complex to regulate gene activation (Wysocka et al, 2005; Migliori et al, 2012). WDR5 is important for mammalian embryonic stem cell (ESC) self renewal and maintenance of active chromatin for pluripotency genes, and WDR5 is required for efficient generation of induced pluripotent stem cells from differentiated somatic cells (Ang et al, 2011; Li et al, 2012)
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