Genetic mutations — changes in the order of the A, C, G, and T nucleotide bases that make up a gene — have been the primary focus of cancer researchers over the last several decades. By sussing out mutations involved in regulating cell growth and division, scientists better understand the molecular range of different cancers and consequently develop more targeted and effective therapeutics.

In recent years, another type of genetic variation has captured the attention of researchers: epigenetic modifications. Best characterized in cancer, epigenetic changes are also thought to play a role in a range of other diseases, including autoimmune disease, cardiovascular disorders, diabetes, neurodegenerative disorders such as Alzheimer’s disease, and potentially even male infertility. In this article, we’ll tell the epigenetics story and discuss how it’s being used to develop new treatments.

Epigenetic modifications are changes to DNA that do not alter the actual gene sequence; they are chemical modifications to the DNA itself. These changes typically affect gene expression or how often the cell reads the gene. Epigenetic modification can occur directly to the nucleotide bases (A, C, G, or T) or to the histones, which are small proteins that package and order DNA.

One of the most common types of epigenetic modification is methylation — the addition of a methyl (CH3) group to cytosine (C) nucleotides. The end result: methylation reduces or even blocks gene expression.

A second type of modification is called acetylation — the addition of an acetyl group (CH3CO) to the histones. Acetylation loosens the association of the DNA with the histones, making the DNA more accessible to the enzymes used in gene expression, ultimately increasing protein production.

Deacetylation — the removal of an acetyl group — increases the association or “grip” of the DNA around the histones. Deacetylation makes the DNA less accessible to enzymes used in gene expression, thereby decreasing the production of proteins.

Epigenetic modification is a normal part of development. This is partly why different genes are expressed in the heart than, say, the liver — the two different tissue types contain the same genome, but tissue-specific differences in epigenetic modification lead to differences in gene expression in the two tissues.

Problems may arise, however, if variations in epigenetic modifications result in changes to gene expression. If a cell or tissue type begins to make too much of a protein that activates cell growth, for example, the cell could begin to divide too often — potentially leading to cancer. Alternatively, a cell could start to make less of a protective protein, such as a “tumor suppressor” protein (a protein that deactivates cell division), potentially leading to cancer.

Epigenetic medicine seeks to identify disease-associated differences in epigenetic modifications and develop drugs that restore the epigenome to healthy cells.

Epigenetic drugs are small molecule drugs that target epigenetic regulators or proteins that write, read, or erase epigenetic modifications.

• Writers are the enzymes that make the chemical modifications — methylation or acetylation as described above — to DNA molecules or histone proteins.
• Erasers are enzymes that remove these chemical groups.
• Readers are the proteins that detect and respond to these modifications, causing the DNA to be more or less tightly wrapped around the histone protein.

Any of these proteins could be inhibited or activated to affect changes in epigenetic modifications.

The disease that has been best classified in terms of epigenetic variations is cancer. Currently, there are five epigenetic drugs on the market to treat cancer, and more are in development. Those on the market fall into two categories – erasers and writers:

• Histone deacetylase (HDAC) inhibitors: HDACs are erasers — they remove acetyl groups from histone proteins, resulting in increased expression of associated genes. The FDA has approved four HDAC inhibitors: Zolinza (Merck; Kenilworth, NJ) and Istodax (Celgene; Summit, NJ) to treat cutaneous T-cell lymphoma, Farydak (Novartis; Basel, Switzerland) treats multiple myeloma and Beleodaq (Spectrum Pharmaceuticals; Henderson, Nevada). HDAC inhibitors in development include those in the table below:

DNA-methyltransferase (DNMT) inhibitors: DNMTs are writers — they add methyl groups to DNA, resulting in decreased expression of associated genes. The FDA has approved two DNMT inhibitors: Vidaza (Celgene) and Dacogen (Otsuka; Tokyo, Japan). Both drugs are used to treat myelodysplastic syndrome and acute myeloid leukemia.

• Histone-methyltransferase (EZH2) inhibitors: EZH2s are also writers — these enzymes transfer methyl groups to histone proteins. One EZH2 is associated with overactivity in several different cancers. There is only one EZH2 inhibitor currently approved, Tazverik developed by Epizyme (Cambridge, MA) for treating patients with epithelioid sarcoma. But several are in development, including Constellation Pharmaceuticals’ (Cambridge, MA) CPI-1205 in Phase II for advanced B-cell lymphomas.

A class of proteins called “Bromodomain and Extra Terminal motif” (BET) proteins are reader proteins. They recognize and bind to specific patterns of acetylation on histone proteins. Upon binding, they recruit additional proteins that regulate gene activity. Then, irregular histone acetylation may send the wrong message to a BET protein. By inhibiting the interaction between BET proteins and histone proteins, researchers have found that they can prevent incorrect messages from being received by the BET proteins. Currently, no BET inhibitors (BBI) are approved, but several are in clinical development. The farthest along is Resverlogix’s (Calgary, Canada) apabetalone, which is in Phase III testing for atherosclerosis and associated cardiovascular disease. Additional BBIs in clinical development are shown in the table below:

Epigenetics promises to change the way we look at the human genome. Scientists have made great strides in understanding how epigenetic modifications contribute to both health and disease; however, a complete understanding of these modifications is still very much a work in progress. As that work develops, researchers will undoubtedly uncover new drug targets and approaches to disease management. Stay tuned!

The intricate dance of epigenetic modifications, from writing and erasing to reading, plays a pivotal role in regulating our genes. While genetic mutations have long been the spotlight of scientific research, the emerging field of epigenetics offers a fresh perspective on understanding diseases and developing innovative treatments. The potential of epigenetic medicine lies in its ability to identify and rectify disease-associated epigenetic modifications, offering a promising avenue for therapeutic interventions. As we continue to unravel the complexities of the epigenome, the horizon looks promising for the development of novel drugs and a deeper understanding of the myriad diseases influenced by these modifications. The journey of epigenetics is just beginning, and its implications for the future of medicine are profound.

1. WHAT ARE EPIGENETIC MODIFICATIONS?

Epigenetic modifications are changes to DNA that do not alter the actual gene sequence. Instead, they are chemical modifications to the DNA or histones that package and order DNA. These modifications can influence gene expression.

2. HOW DO EPIGENETIC MODIFICATIONS DIFFER FROM GENETIC MUTATIONS?

Genetic mutations involve changes in the order of the A, C, G, and T nucleotide bases that make up a gene. In contrast, epigenetic modifications do not change the gene sequence but rather modify the DNA or associated histones, influencing how genes are expressed.

3. WHAT ARE THE MAIN TYPES OF EPIGENETIC MODIFICATIONS DISCUSSED IN THE ARTICLE?

The article mentions methylation, where a methyl group is added to cytosine nucleotides, and acetylation, where an acetyl group is added to histones. Deacetylation, the removal of an acetyl group, is also discussed.

4. HOW DO EPIGENETIC MODIFICATIONS CONTRIBUTE TO DISEASES LIKE CANCER?

Answer: Variations in epigenetic modifications can lead to changes in gene expression. For instance, if a cell starts producing too much of a protein that promotes cell growth, it could divide excessively, potentially leading to cancer. Conversely, reduced production of a protective protein, like a tumor suppressor, could also lead to cancer.

5. WHAT ARE THE THREE MAIN CATEGORIES OF EPIGENETIC REGULATORS?

The three main categories are writers, erasers, and readers. Writers make chemical modifications to DNA molecules or histone proteins. Erasers remove these chemical groups. Readers detect and respond to these modifications, influencing how DNA is wrapped around the histone protein.

6. ARE THERE ANY APPROVED DRUGS THAT TARGET EPIGENETIC MODIFICATIONS?

Yes, there are several approved drugs, particularly for cancer. For instance, there are HDAC inhibitors like Zolinza and Istodax, DNMT inhibitors like Vidaza and Dacogen, and an EZH2 inhibitor called Tazverik.

7. WHAT IS THE POTENTIAL OF BET INHIBITORS IN EPIGENETIC MEDICINE?

BET proteins are reader proteins that recognize and bind to specific acetylation patterns on histone proteins. Researchers can potentially prevent incorrect gene regulation messages by inhibiting the interaction between BET proteins and histone proteins. While no BET inhibitors are currently approved, several are in clinical development.