Chromatin Modifications and Their Function

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Regulation of chromatin by histone modifications

http://www.people.vcu.edu/~mreimers/SysBio/Li%20-%20Role%20of%20chromatin%20in%20transcription.pdf

The Role of Chromatin during Transcription

An important development in understanding the influence of chromatin on gene regulation has been the finding that DNA methylation and histone post-translational modifications lead to the recruitment of protein complexes that regulate transcription. Early interpretations of this phenomenon involved gene regulation reflecting predictive activating or repressing types of modification. However, further exploration reveals that transcription occurs against a backdrop of mixtures of complex modifications, which probably have several roles. Although such modifications were initially thought to be a simple code, a more likely model is of a sophisticated, nuanced chromatin 'language' in which different combinations of basic building blocks yield dynamic functional outcomes.

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The complex language of chromatin regulation during transcription

The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.

The Biology of Chromatin Remodeling Complexes

Acetylation of histone H4 on lysine 16 (H4-K16Ac) is a prevalent and reversible posttranslational chromatin modification in eukaryotes. To characterize the structural and functional role of this mark, we used a native chemical ligation strategy to generate histone H4 that was homogeneously acetylated at K16. The incorporation of this modified histone into nucleosomal arrays inhibits the formation of compact 30-nanometer-like fibers and impedes the ability of chromatin to form cross-fiber interactions. H4-K16Ac also inhibits the ability of the adenosine triphosphate-utilizing chromatin assembly and remodeling enzyme ACF to mobilize a mononucleosome, indicating that this single histone modification modulates both higher order chromatin structure and functional interactions between a nonhistone protein and the chromatin fiber.

https://science.sciencemag.org/content/sci/311/5762/844.full.pdf

Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions

A native peptide ligation strategy for deciphering nucleosomal histone modifications

How post-translational histone modifications regulate DNA utilization constitutes one of the central questions of chromatin biology. In studying the mechanistic role of histone H4-K16 acetylation, a mark with a functional role in maintaining transcriptionally permissive DNA domains or directly promoting gene transcription, we found that this acetylation both disrupts higher-order chromatin structure and changes the functional interaction of chromatin-associated proteins. The potential significance of this finding for in vivo chromatin structure, establishment of euchromatic domains, and promotion of gene transcription is examined.

Switching on Chromatin: Mechanistic Role of Histone H4-K16 Acetylation

Publisher Summary Histones in all eukaryotic organisms are enzymatically altered to present a wide range of posttranslational modifications, including acetylation, phosphorylation, methylation, ubiquitination, and ribosylation. To probe how posttranslational modifications of histones influence both chromatin structure and the binding, and function of chromatin-associated proteins, this chapter describes a strategy that employs native chemical ligation1,2 to generate designed histones and the protocol used for the synthesis and purification of modified histone H3 tail thioester peptides, the generation of amino-terminal cysteine-containing histone H3 core protein, and the ligation of these constituents. This strategy, in principle, can be used to study virtually any histone modification and offers a number of advantages over alternative methods. Unlike enzymatically modified histones or those purified from cellular lysates, ligation provides homogeneously modified histones. Furthermore, because these synthetic histones can be readily assembled in vitro into chromatin, they are more physiologically relevant than peptide substrates.

Creating designer histones by native chemical ligation.

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Michael Shogren-Knaak

Papers

Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions

A native peptide ligation strategy for deciphering nucleosomal histone modifications

Switching on Chromatin: Mechanistic Role of Histone H4-K16 Acetylation

Creating designer histones by native chemical ligation.

Histone H3 amino-terminal tail phosphorylation and acetylation: synergistic or independent transcriptional regulatory marks?