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Epigenetics: A new science rewriting history of disease; our genome is only part of the story. The other part is the epigenome.

Our DNA—the 25,000 genes identified by the Human Genome Project—is now widely regarded as the instruction book for the human body. But genes themselves need instructions for what to do, and where and when to do it. That’s where the epigenome comes into play; it assists in controlling gene regulation.

The DNA strand in each cell, like thread around a spool, is wound around a protein complex called the histone. This process is necessary to compact the DNA to fit into the nucleus of the cell. The DNA and the histone protein complex are collectively referred to as chromatin. Changes in chromatin structure due to either chemical modification of the DNA (methylation) or changes in DNA-histone interactions help control gene expression, silencing or activating genes. Improper gene expression ultimately leads to the improper production or non-production of proteins which are the source of most diseases and disorders.

Source:  nihroadmap.nih.gov

This spooling around histones enables two meters-worth of DNA to fit inside the nucleus of a cell. But, the coiling of the DNA strand makes it difficult for genes to be expressed. Various chemical modifications to the histones cause the DNA to wrap more tightly or loosely around the histones. These chemical modifications are directly responsible for making the DNA accessible or inaccessible to control gene regulation.

For example, if the DNA is erroneously wrapped too tightly around the histone, the DNA’s sequence of nucleotides is not accessible and cannot easily be transcribed. If a tumor suppressor gene is not expressed – due to incorrect epigenetic regulation – apoptosis cannot occur and the abnormal cells continue to develop and may metastasize. Conversely, if the DNA is wrapped too loosely, DNA that should not be expressed is erroneously transcribed, conferring yet another set of consequences leading to disease. If the gene is an oncogenic gene that should be silenced and is aberrantly expressed, a tumor may grow.

Supporting this theory, recent research has identified enzymes responsible for the process called “histone post translational modifications.” This research has identified specific enzymes and illuminated the importance of their impact on DNA-histone interactions. The post translational modifications which usually take place on the “tails” of histones include methylation, acetylation, phosphorylation and ubiquitination. These modifications control the tightness of the DNA around the histone proteins and, consequently, gene expression. Furthermore, an increasing number of these newly identified enzymes have been associated with neurodegenerative disorders, metabolic diseases, inflammation, and most notably, cancer.

With this new breakthrough understanding of how genes are expressed, Constellation will be developing highly selective drugs directed against the enzymes that regulate these histone modifications, promising a novel approach to the treatment of human disease.