Histone deacetylase

Histone deacetylases (HDAC) (EC number 3.5.1) 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.

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Functions

Deacetylation removes acetyl groups from histone tails, causing the DNA to wrap more tightly around the histones and interfering with the transcription of genes by blocking access by transcription factors. The overall result of histone deacetylation is a global (non specific) reduction in gene expression.

Histone tails are normally positive charged. The positive charge in them helps them interact very nicely and tighly to the negative charged DNA. Acetyl neutralize the positive charge in the histone; making its interaction with DNA less tight. Thus, dacetylation removes the acetyl groups and restores the positive charge of the histones.

Histone Deacetylase involved in a series of pathway in the living system. In Kyoto Encyclopedia of Genes and Genomes (KEGG), they 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 regulation of gene expression. Hyperacetylated chromatin is transcriptionally active and hypoacetylated is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1^[1] Their study also found a regulatory cross talk 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,^[2] negatively correlating with the expression of GAD67 mRNA.

HDAC inhibitors

HDAC inhibitors (HDIs) are being studied as a treatment for cancer and neurodegenerative diseases^[3]. The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.^[4]

HDAC inhibitors may also be associated with the inhibition of some gene promoters. However, this could be due to increased activity of other negative-regulatory proteins.

Family

Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.^[5][6]

Classes of HDACs in higher eukaryotes

HDACs, depending on sequence identity and domain organization, can be organized in three classes:^[7]

• Class I

HDAC1

HDAC2

HDAC3

HDAC8

• Class II

HDAC4

HDAC5

HDAC6

HDAC7 (HDAC7A)

HDAC9

• Class III

Homologs of Sir2 in the yeast Saccharomyces cerevisiae, or sirtuins

See also

• Histone-Modifying Enzymes
• Histone methyltransferase
• RNA polymerase control by chromatin structure

References