Histones and Histone Deacetylases

Epigenetics is an increasingly big deal in biological discovery. We are regularly reading about the influence of actions peripheral to DNA in regulating DNA transcription and translation. We are learning that mice may fear what grandparent mice feared (Kelly’s blog ), due to heritable changes in DNA. In term of one of several mechanisms of epigenetic change, we are learning much about histone deacetylases and their role in gene regulation, as well as disease (Isobel’s blog ). In this blog, let’s take a step back and look at histones, and how they are influenced by acetylation/deacetylation.

The Role of Histones
Histones are proteins found in the nucleus of eukaryotic cells, where they package DNA into nucleosomes. Histones make up the main protein component of chromatin, acting as spool-like structures around which DNA wraps.

There are five major histone classes,three of these are core histones, the other two are called linker histones. Core histones comprise the core of the nucleosome, around which DNA is wrapped, while the linker histones bind at the entrance and exit sites of the DNA, so as to lock it into place. The linker histones also enable a higher order of structure. If you hold both ends of a rubber band, and twist one end, you’ll see that the rubber band twists and folds over itself; the end being held steady enables this twisting and folding: this is how the linker histones work. Histone-DNA structure is frequently represented as a beaded chain-type image (see figure).

DNA wrapping around histones in a bead and chain-like fashion.
DNA wrapping around histones in a bead and chain-like fashion.

Histone and DNA: Charged Interactions
Histone tails normally carry a positive charge due to amine groups present on their lysines and arginines. This positive charge is the means by which histone tails interact with and bind to the negatively-charged phosphate groups on the DNA backbone.

Histones are subject to post-translational modifications, primarily on their N-terminal tails, by enzymes. Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. Such modifications can affect histone function in gene regulation. Acetylation is one of the most common post-translational modifications of histones (1).

Acetylation Affects Transcription
Acetylation occurs normally in cells. Addition of acetyl groups neutralizes the positive charges on the histone by changing amines into amides, thus decreasing the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove the acetyl groups, increasing the positive charge of histone tails and thus high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.

To summarize, acetylation decreases DNA-histone binding, allowing transcription, while deacetylation increases DNA-histone binding, condensing the DNA structure, and thus blocking transcription.

“Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1 (3) .”

About HDAC
Histone deacetylases or HDAC are enzymes found in most eukaryotic cells. They remove acetyl groups from N- terminal lysines on histones, allowing the histones to wrap the DNA more tightly. HDAC proteins have more recently become known as lysine deacetylases or KDAC, to describe their function rather than their target (2). Speaking of HDAC targets, it is interesting to note that HDACs also work to deacetylate non-histone proteins (2).

Histone deacetylase is involved in a series of pathways in living systems, including signal transduction and cell death and replication. In addition , HDAC is increasingly being implicated in diseases, such as chronic myelogenous leukemia (2, 3).

1. de Ruijter, A.J.  et al. (2003) Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J. 370, 737. PMID:12429021
2. Brandl, A. et al.(2009) Histone deacetylases: salesmen and customers in the post-translational modification market. Biol Cell. 101(4):193. PMID:19207105
3. Zupkovitz, G. et al. (2006) Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase 1. Mol. Cell. Biol. 26 (21): 7913–28. PMID 16940178

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Kari Kenefick

Kari Kenefick

Kari has been a science writer/editor for Promega since 1996. Prior to that she enjoyed working in veterinary microbiology/immunology, and has an M.S. in Bacteriology, U of WI-Madison. Favorite topics include infectious disease, inflammation, aging, exercise, nutrition and personality traits. When not writing, she enjoys training her dogs in agility and obedience. About the practice of writing, as we say for cell-based assays, "add-mix-measure".

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