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Defining epigenetic states through chromatin and RNA

Nature Genetics volume 37, pages 917–918 (2005)Cite this article

Nucleosomal histones are the target of a variety of post-translational modifications, including acetylation, phosphorylation, ubiquitination and methylation. These alterations regulate accessibility for DNA binding proteins and create recognition signals to anchor protein complexes. Despite intensive study, we know little about how the bulk of the potential modification repertoire is used, what the function of individual or combined modifications is or how modifications are targeted to specific domains or loci. One recent research focus is the dynamics of histone methylation, involved in both gene activation and repression, depending on the modified amino acid. The extent of modification can vary, for example, between mono-, di- and trimethylated lysine. Methylation at Lys4 of histone H3 (H3K4me), typical of the active state, is mediated in vertebrates by the complexes MLL1, MLL2 and hSet1, which all share the WD40 domain protein WDR5. Joanna Wysocka (New York, USA; with C. David Allis, New York, USA) showed that WDR5 directly interacts with H3K4me2 and can enhance transcription if tethered to a reporter gene. Knock-down of WDR5 leads to selective reduction of H3K4me3, as opposed to H3K4me2, but does lead to developmental defects in Xenopus laevis embryos. As a cofactor required for H3K4me3, WDR5 may help to propagate an active state by both recognizing the dimethylated form and promoting trimethylation, providing a parallel to the well-known role of HP1 in supporting heterochromatin formation2. Such patterns of interaction between modified histones and histone modifiers may be inherent to epigenetic regulation of gene expression at the domain level, a paradigm distinct from those operating in prokaryotes.

Modification of neighboring residues can block or enhance individual histone modifications, suggestive of obligate pathways of modification with enhanced regulatory potential. In a new twist, Tony Kouzarides (Cambridge, UK) discussed the impact of proline isomerization on H3K36me, a modification that has been implicated in regulation of the elongating RNA polymerase II3. Peptidyl-prolyl-isomerases catalyze the conversion of proline from cis to trans form, altering the peptide backbone configuration. The enzyme FPR4 can isomerize H3 Pro38 in vitro; Pro38 appears to be required for K36me in vivo. This result suggests that the cis-trans isomerization of proline peptide bonds could be a regulated process that might occur upstream of covalent histone modification.

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Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Basel, 4058, Switzerland

    Dirk Schübeler

  2. Department of Biology, Washington University, St. Louis, 63130, Missouri, USA

    Sarah C R Elgin

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  1. Dirk Schübeler
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  2. Sarah C R Elgin
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Schübeler, D., Elgin, S. Defining epigenetic states through chromatin and RNA. Nat Genet 37, 917–918 (2005). https://doi.org/10.1038/ng0905-917

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