This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Post-translational modification of histones by phosphorylation, acetylation, and methylation plays a key role in transcriptional regulation, but also directs other cellular DNA-mediated processes. Histone modifications can act as signaling marks, recruiting specific protein-binding modules. These mediate functional readout and translate distinct histone modification states into biologically meaningful function. For example, bromodomain-containing proteins, such as pCAF, GCN5, and TAF250, have been shown to bind to several acetyl-lysine residues in core histones H3 and H4, thereby mediating transcriptional activation. Furthermore, the chromodomain proteins HP1 and Polycomb (Pc), have been implicated in the recognition of individual methylated lysine residues, namely H3-lysine 9 and H3-lysine 27, thereby mediating the formation of silenced states of chromatin. The modification of histone lysine residues by methylation has enormous signaling potential, as lysines can be mono-, di-, or tri-methylated. These different modification stages are directed by different histone methyltransferases and are targeted to distinct domains of chromatin. We report below on structures of peptide-protein complexes that define state-specific recognition of methylated K4 on H3 by WDR5, a WD40 module and the PHD finger of BPTF. Trimethylation of K4 on H3 has been linked to transcriptional activation in a range of eukaryotic species.
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