Seeing beyond the double helix.

Epigenetics, or heritable changes not encoded in the DNA sequence, is a phenomenon important for an overall increase in the complexity of the genome without changes in gene sequence. Our complete genome is contained in each of our cells. Corneal cells are different than nerve cells due to a usage pattern of the genome that is maintained in a cellular memory of active or repressed genes. These “on and off switches” for our genes are often determined by factors outside the genomic DNA sequence. Some of the main controlling mechanisms known today are the methylation of DNA and information embedded in the histone proteins that package the genomic DNA. DNA is wrapped around the four core histones, H2A, H2B, H3, and H4, into the physiological form of the genome called chromatin. Post-translational modifications (PTMs) of these histones, and deposition of histone variants, form a “histone code” of activation or repression of transcription. The histone code and DNA methylation constitute the epigenome (“on top of the genome”). The epigenome’s importance is now well established in the clinic for understanding the etiology of developmental defects, congenital diseases, and many cancers. What are the writers, readers, and erasers of the histone code? Core histones and histone variants are assembled with DNA to form chromatin via histone chaperones and ATP-dependent histone motor proteins. Histone PTMs are “written” by large families of enzymes, including histone acetyltransferases (HATs), lysine methyltransferases (KMTs), and arginine methyltransferases (PRMTs). PTMs are recognized and acted on by “readers” of the code, which are proteins that specifically bind to the PTMs and elicit a downstream biological response by altering usage of the underlying DNA. “Erasers,” such as lysine demethylases (KDMs) and histone deacetylases (HDACs), remove the histone PTMs from histones embedded in the chromatin. Many drugs in use and in development target the writers, readers, and erasers of histone PTMs for a variety of clinical indications. They are currently targeted primarily toward cancers. These classes of drugs will see increasing use in the future. How does the histone code function in eye development and disease? An epigenetically encoded cellular memory maintains cells in their differentiated state through the writers, readers, and erasers described above. For instance, the specific transcription factors that regulate eye development recruit HATs, KMTs, KDMs, and HDACs through histone code readers to establish and maintain this histone code epigenetic memory. Because many ocular diseases are age-dependent, acquired aberrations in this epigenetic code may be causal for disease onset.