Sunday 23 November 2003
Histones, nuclear proteins that bind DNA and form nucleosomes, are directly involved with both the packaging of DNA into chromosomes and the regulation of transcription. Histone acetylation/deacetylation is a major factor in regulating chromatin structural dynamics during transcription.
DNA methylation, histone deacetylation, and methylation of histone H3 at lysine 9 are the three best-characterized covalent modifications associated with a repressed chromatin state. Histone deacetylation and methylation at lysine 9 of H3 might also contribute to the establishment of DNA methylation patterns.
Acetylation of histone
Acetylation of histone proteins correlates with transcriptional activation and a dynamic equilibrium of histone acetylation is governed by the opposing actions of HATs and histone deacetylases (HDACs).
Aside from histones, many transcriptional regulators, chromatin modifiers, and intracellular signal transducers are posttranslationally modified by acetylation. Both HATs and HDACs have been found mutated or deregulated in various cancers.
The two closely related HATs, p300 and CBP, act as transcriptional cofactors for a range of cellular oncoproteins, such as MYB, JUN, FOS, RUNX, BRCA1, p53, and pRB, as well as for the viral oncoproteins E1A, E6, and SV40 large T.
CBP and p300 are functional tumor suppressors as demonstrated by several lines of evidence. Both genes reside in regions frequently lost in tumors, and cancer-specific mutations abolishing the enzymatic activity of p300 have been identified.
CBP and p300 are found disrupted by translocations in leukemia with translocation partners including MLL, MOZ, and MORF.
Germ-line mutations in CBP causes the developmental disorder Rubenstein-Taybi syndrome, and these patients suffer an increased cancer risk. Finally, genetic ablation studies of Cbp and p300 in mouse models have confirmed that both proteins function as tumor suppressors.
HDACs have, not unlike DNA methylation, dualistic and opposite functions in cancer development. On the one hand, HDACs play prominent roles in the transcriptional inactivation of tumor-suppressor genes.
This is evident from studies using pharmacological inhibitors of HDAC activity in cancer therapies (discussed following). On the other hand is the reliance of important tumor-suppressor mechanisms on HDAC function, as exemplified by the dependency of RB on HDAC1 for transcriptional repression of E2F target genes.
Hdac1-deficient mice are not viable and ES cells with homozygous Hdac1 deletion display proliferation defects correlating with increased levels of the cyclin-dependent kinase inhibitors p21 (CDKN1A) and p27 (CDKN1B), demonstrating the involvement of HDAC1 in cell cycle regulation.
In mice, Hdac2 is genetically linked to the Wnt pathway, as Hdac2 is overexpressed in tumors and tissues from mice lacking the adenomatosis polyposis coli (APC) tumor suppressor.
Likewise, RNAi-mediated knockdown of HDAC2 in colonic cancer cells resulted in cell death, indicating a role for HDAC2 in protecting cancer cells against apoptosis.
Importantly, HDACs are associated with a number of other epigenetic repression mechanisms, including histone methylation, PcG-mediated repression (van der Vlag and Otte 1999), and DNA methylation.
Importantly, HDAC activity is often crucial to prepare the histone template for methyltransferases by removing acetyl groups obstructing methylation. HDACs are, moreover, often found as "partners in crime" when captured by oncoproteins such as PML-RAR or AML-ETO to induce aberrant gene silencing.
The researchers discovered an alteration in a gene called HDAC9 that affects a person’s risk of large artery ischaemic stroke. This variant occurs on about 10 per cent of human chromosomes. Those people who carry two copies of the variant (one inherited from each parent) have nearly twice the risk for this type of stroke than those with no copies of the variant.
The protein produced by HDAC9 is already known to have a role in the formation of muscle tissue and heart development; however, the exact mechanism by which the genetic variant increases the risk of stroke is not yet known.
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