Histone Protein of interest for 21st Century

Many of the major human diseases, such as cancer, heart, neurodegenerative and psychiatric disorder correlated with modifications in the residues region of histone pos-translational modification. The residues in the N-terminal region of histone are covalentely modified by acetylation, methylation and phosphorylation. Histone is normally modified by acetylation reaction catalyzed by histone enzyme acetyltransferase (HAT). This process can make the structure of chromatin to open and facilitate transcription process. Also, the reaction can be catalyzed in the opposite direction (is reversible) by the histone enzyme deacetylase (HDAC) and it removed acetyl groups and then changed the conformation of chromatin to close, and this could possible turn genes off and thus making transcription unavailable. Some studies found that histone deacetylase enzyme plays a major role in DNA methyltransferases in silencing tumor suppressor genes. For instance, methylation of lysine 9 on histone H3 can turn genes off by changing a chromatin configuration whereas methylation of lysine 4 on histone H3 is turning genes on(Abel, 2008 and Filipe,2010).  The researchers saw histone methylation, DNA methylation as epigenetic mechanisms that could block the expression of tumor suppressor genes. It can be a potential therapeutic for cancer, neurodegenerative disorder and heart disease.

 

Figure: Acetylation and deacetylation of lysine residues.

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3380189_12263_2012_283_Fig1_HTML.jpg

References

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405764/

 

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25482/full

Third Article

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101110/pdf/cmr-3-117.pdf

 According to Martinet and Phillipe,  histones are proteins that wrap up the nuclear DNA and constitute a superstructure named chromatine which builds dynamic units called nucleosomes. The four core histones: H2A, H2B, H3 and H4, form an octameric histone surrender with 147 base pairs of DNA, and linked by histone H1.  The chromatine architecture is modified by histone acetyltransferases (HATs): Acetylation and deacetylation of specific lysine residue of histone.  This process can express or repress genes.

The comformation modification by histones produce “histone code”.  For instance. K9 in H3 converts chromatine into inactive form when methylated, phosphorylation of serine 10 is the same H3 that is needed for methylation of K4 and acetylation of K9 and K14. 

This research paper has shown that histone deacetylase inhibitor as a possible way to treat the human life threating diseases.  For instance, In October 2006 the FDA approved vorinostat (HDACi drug) for the treatment of advanced forms of cutaneous T-cell lymphoma.  But there are still some research requirements to approve bioactivity in vitro and in vivo of HDACi.