Histone Deacetylation

Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferase.
Subtypes

HDAC proteins are found in three groups, the first two groups belong to the classical HDACs and their activities are inhibited by trichostatin A (TSA) whereas the third group is a family of NAD+-dependent proteins not affected by TSA. Homologues to all three groups are found in yeast having the names reduced potassium dependency 3 (Rpd3) - corresponds to class 1, histone deacetylase 1 (hda1) – to class 2 and silent information regulator 2(Sir2) – class3.



Function

Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This process allows chromatin expansion, allowing for genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. This process condenses DNA structure, preventing transcription.

Histone deacetylase is involved in a series of pathways within the living system. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), these are:

  • Environmental information processing; signal transduction; notch signaling pathway PATH:ko04330
  • Cellular processes; cell growth and death; cell cycle PATH:ko04110
  • Human diseases; cancers; chronic myeloid leukemia PATH:ko05220

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.[5] Their study also found a regulatory crosstalk between HDAC1 and HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,negatively correlating with the expression of GAD67 mRNA.

It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational_modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein_kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogus mechanism, in which non-histone proteins are acted on by acetylases and deacetylases . It is in this context that HDACs are being found to interact with a variety of non-histone proteins -- some of these are transcription factors and co-regulators, some are not. Note the following four examples:
  •  HDAC6 is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.
  •  PTEN is an important phosphatase involved in cell signaling via phosphoinositols and the AKT/PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (PCAF) can stimulate its activity; conversely, deacetylation of PTEN by SIRT1 deacetylase and apparently by HDAC1 can repress its activity.
  •  APE1/Ref-1 (APEX) is a multifunctional protein possessing both DNA repair activity (on abasic and single strand break sites) and transcriptional regulatory activity associated with oxidative stress. APE1/Ref-1 is acetylated by PCAF; conversely it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its DNA repair activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormone gene.
  •  NF-kB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via HDAC3 and HDAC6.

These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.

HDAC inhibitors
Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epilectics, for example, valproic acid. More recently, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.Also in recent years, there has been an effort to develop HDIs for cancer therapy, and Vorinostat (SAHA) has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed. In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.

HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and thereby increase or repress their activity. For the four examples given above (see Function) on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1.[

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