Readout of Epigenetic Modifications.
ABSTRACT This review focuses on a structure-based analysis of histone posttranslational modification (PTM) readout, where the PTMs serve as docking sites for reader modules as part of larger complexes displaying chromatin modifier and remodeling activities, with the capacity to alter chromatin architecture and templated processes. Individual topics addressed include the diversity of reader-binding pocket architectures and common principles underlying readout of methyl-lysine and methy-larginine marks, their unmodified counterparts, as well as acetyl-lysine and phosphoserine marks. The review also discusses the impact of multivalent readout of combinations of PTMs localized at specific genomic sites by linked binding modules on processes ranging from gene transcription to repair. Additional topics include cross talk between histone PTMs, histone mimics, epigenetic-based diseases, and drug-based therapeutic intervention. The review ends by highlighting new initiatives and advances, as well as future challenges, toward the promise of enhancing our structural and mechanistic understanding of the readout of histone PTMs at the nucleosomal level. Expected final online publication date for the Annual Review of Biochemistry Volume 82 is June 02, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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ABSTRACT: Post-translational modifications (PTMs) of histones constitute a major chromatin indexing mechanism, and their proper characterization is of highest biological importance. So far, PTM-specific antibodies have been the standard reagent for studying histone PTMs despite caveats such as lot-to-lot variability of specificity and binding affinity. Herein, we successfully employed naturally occurring and engineered histone modification interacting domains for detection and identification of histone PTMs and ChIP-like enrichment of different types of chromatin. Our results demonstrate that histone interacting domains are robust and highly specific reagents that can replace or complement histone modification antibodies. These domains can be produced recombinantly in Escherichia coli at low cost and constant quality. Protein design of reading domains allows for generation of novel specificities, addition of affinity tags, and preparation of PTM binding pocket variants as matching negative controls, which is not possible with antibodies.Genome Research 10/2014; DOI:10.1101/gr.170985.113 · 13.85 Impact Factor
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ABSTRACT: Chromatin dynamics play an essential role in regulating the accessibility of genomic DNA for a variety of nuclear processes, including gene transcription and DNA repair. The posttranslational modification of the core histones and the action of ATP-dependent chromatin remodeling enzymes represent two primary mechanisms by which chromatin dynamics are controlled and linked to nuclear events. Although there are examples in which a histone modification or a remodeling enzyme may be sufficient to drive a chromatin transition, these mechanisms typically work in concert to integrate regulatory inputs, leading to a coordinated alteration in chromatin structure and function. Indeed, site-specific histone modifications can facilitate the recruitment of chromatin remodeling enzymes to particular genomic regions, or they can regulate the efficiency or the outcome of a chromatin remodeling reaction. Conversely, chromatin remodeling enzymes can also influence, and sometimes directly modulate, the modification state of histones. These functional interactions are generally complex, frequently transient, and often require the association of myriad additional factors. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 08/2014; DOI:10.1016/j.bbagrm.2014.02.013 · 5.44 Impact Factor
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ABSTRACT: The regulatory role of histone modifications with respect to the structure and function of chromatin is well known. Proteins and protein complexes establishing, erasing and binding these marks have been extensively studied. RNAs have only recently entered the picture of epigenetic regulation with the discovery of a vast number of long non-coding RNAs. Fast growing evidence suggests that such RNAs influence all aspects of histone modification biology. Here, we focus exclusively on the emerging functional interplay between RNAs and proteins that bind histone modifications. We discuss recent findings of reciprocally positive and negative regulation as well as summarize the current insights into the molecular mechanism directing these interactions. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function, edited by Dr. Wolfgang Fischle.Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 08/2014; DOI:10.1016/j.bbagrm.2014.03.015 · 5.44 Impact Factor