October 1, 2018 (Vol. 38, No. 17)

Surging Knowledge of Epigenetic Mechanisms May Sweep Epigenetic Drugs

In a relatively short time, epigenetics has transformed our understanding of inheritance, development, and disease progression. By revealing the epigenetic mechanisms behind many diseases, epigenetic research shows the potential for targeting these mechanisms with new treatments, epigenetic drugs.In the 2000s, the first FDA-approved epigenetic drugs appeared, and they have been raising hopes ever since. (For example, back in 2006, Time magazine published a cover story entitled, “Why your DNA isn’t your destiny.”) Epigenetics now sits squarely at the forefront of novel drug discovery, with promises of treatments for cancer and other diseases.

The most widely studied epigenetic mechanisms—DNA methylation, histone modification, and chromatin remodeling—are critical for gene and noncoding RNA expression. Moreover, these mechanisms are responsible for the sum of a person’s epigenetic marks, that is, the person’s epigenome.

To analyze large-scale genomic and epigenomic data, researchers, drug developers, and clinical scientists have been combining new kinds of assays, specialized sequencing methods, and more powerful bioinformatics technology. As a result, they have been identifying epigenomic disease modifications, leading to a new appreciation of its role in human disease. They have found that cancer is, by far, the largest area where epigenetics is implicated. They have also shown that epigenetics has a role in some neurological disorders and autoimmune diseases.

Alzheimer’s Disease as an Epigenetic Disease

The translational science occurring in the Katz Lab at the Emory University School of Medicine surprises no one more than the head of the lab, David J. Katz, Ph.D. A classically trained developmental geneticist, whose interest lies in the development of the germline of the roundworm Caenorhabditis elegans, Dr. Katz has channeled his lab’s work into the study of histone methylation. The lab examines how this mechanism influences cell fate, as well as how this mechanism can go awry.

The lab focuses largely on the first identified histone demethylase, lysine-specific demethylase 1 (LSD1). Already, the lab has shown that LSD1 is required in the germline to reprogram histone H3K4 methylation. In addition, the lab has shown how this pathway prevents epigenetic transcriptional memory from being inherited transgenerationally.

When Dr. Katz and colleagues moved their work into a mouse model, they inadvertently discovered massive neurodegeneration and paralysis when LSD1 was eliminated from adult mice. One experiment resulted in their mice having massive neurodegeneration and paralysis, leading to the model that LSD1 plays a role in Alzheimer’s disease (AD) and a related condition, frontotemporal dementia. Indeed, when an LSD1 antibody was applied to postmortem AD patient’s brains, it colocalized with tau protein aggregates—the hallmark of AD. This was a remarkable result as very few proteins have been shown to colocalize with aggregates.

Dr. Katz anticipates that his lab’s work will advance drug discovery through epigenetics. If no other company exploits the work, his will, even though it currently exists only on paper.

“Most of the epigenetic drugs are cancer therapies,” he notes. “More recently, drugs that target epigenetic enzymes have been pursued for a wide range of diseases, ranging from muscular dystrophies to Alzheimer’s disease. Going forward, it will be exciting to see if epigenetic-based therapies prove to be effective against other diseases.”

Key Epigenetic Findings from Ants

Ants are a powerful model to study epigenetics. Why? Because different types of ants in the colony arise from the same genome. “Workers and queens have the same genes,” points out Roberto Bonasio, Ph.D., an assistant professor of cell and developmental biology at University of Pennsylvania’s Perelman School of Medicine. “Among other things,” he tells GEN, “this means that the same genome specifies at least two types of brain that behave in dramatically different ways.” If we study how epigenetics influences the brains of ants, we might gain insights of general significance.

Dr. Bonasio started his postdoc intending to use biochemical methods to study gene regulation, but the rise of new technology changed his plans. “The deep sequencing revolution came,” he recalls, “so everything went from single locus and in vitro systems to genome-wide in vivo.” Now it is hard, he continues, “to find a chromatin and epigenetics paper without lots of genomics and bioinformatics.”

He is particularly excited by new work suggesting that noncoding RNAs in the nucleus influence transgenerational epigenetic inheritance. This work, which is highly controversial, challenges the longstanding notion that most if not all epigenetic marks are erased in the germline (at least in mammals), such that every new individual starts with a clean genomic slate.

To study whether noncoding RNAs carry epigenetic information across generations, Dr. Bonasio focuses heavily on genomics, which he thinks may be the “most transformative new approach in epigenetics.” For example, he relied on genomics in recent studies of two ant species, Camponotus floridanus and Harpegnathos saltator. He reassembled de novo high-quality genomes, and then he annotated long noncoding RNAs (lncRNAs). In H. saltator, he discovered that the expression of lncRNAs differs across developmental stages, as well as in the brains of ants of different castes.

Epigenetic-Based Drug Development

The lab of Giacomo Cavalli, Ph.D., the head of the Institute of Human Genetics at the French National Center for Scientific Research in Montpellier, France, works to understand 3D genome organization and its functional implications. Specifically, the lab studies the molecular mechanisms of two main groups of genome regulatory proteins: the polycomb group, which includes gene-repressing histone-modifying enzymes, and the trithorax group, which includes gene-activating histone-modifying enzymes. These proteins, which have been known for roughly a century, influence the genome’s 3D organization.

Functionally, polycomb and trithorax proteins regulate the genes that convey inheritance of chromatin states and orchestrate development. They can also, as Dr. Cavalli discovered in Drosophila melanogaster, play a role in transgenerational inheritance of chromatin states.

Besides maintaining basic epigenetic processes, polycomb and trithorax “have major roles in human disease,” says Dr. Katz. He adds that “even before the discovery that epigenetic modifications have a role in human disease, early fruit fly investigators had evidence that epigenetic enzymes could be targeted to reverse defects caused by epigenetic perturbations. This is why epigenetic drug targets are so promising.”

Dr. Cavalli is quick to point out the advantages to drug design based on epigenetics. He tells GEN, “Many cancers and other diseases depend not only on mutations, but mainly on altered levels of expression of epigenetic modulators.” Therefore, “an epigenetic drug might correct the problem.” He adds that “epigenetic component variations are well tolerated in normal tissues as long as critical thresholds are not crossed, suggesting a relatively low toxicity for these drugs,” and that “combination with established drugs acting on other principles is very promising since they leverage different and frequently orthogonal cell processes.”

However, targeting epigenetic mechanisms for drug development brings its own unique challenges. “For the moment,” Dr. Cavalli advises, “specificity is an issue in many cases.” Dr. Katz adds that “epigenetic modifying enzymes work on many genes,” so “there is the potential to cause changes in other genes that were not originally affected by the disease, potentially leading to unanticipated side effects.” Dr. Cavalli cautions that “these drugs will have to be carefully tested and not blindly transported from the treatment of one to another disease.”

As for future developments, Dr. Cavalli says to look for “more selective and sensitive histone methyltransferase inhibitors, particularly for EZH2.” He adds that we will likely see “improvement in BET inhibitors and in DNA methylation, with TET inhibitors as well as mutated IDH inhibitors to watch out for.” He adds that “modulators of SWI/SNF complexes are also quite exciting.”

This last point, he suggests, would meet with the approval of Cigall Kadoch, Ph.D., assistant professor of pediatric oncology at the Dana-Farber Cancer Institute. As it happens, when GEN caught up with Dr. Kadoch, she concurred with Dr. Cavalli.

Cigall Kadoch, Ph.D., assistant professor of pediatric oncology at the Dana-Farber Cancer Institute, studies the BAF complex, which regulates chromatin structure. Although the BAF complex has been credited with protecting cells against cancer, aberrant versions of BAF have been implicated in rare, hard-to-treat cancers such as synovial sarcoma and malignant rhabdoid tumors. In a recent study from Dr. Kadoch’s lab, BAF complexes were shown to be mutated in more than 20% of human cancers.

A New Class of Epigenetic Targets

When Dr. Kadoch joined Stanford University’s Crabtree Lab, it was not focused on the study of cancer. Rather, it was devoted to improving our understanding of development and differentiation. Specifically, it was scrutinizing the chromatin remodeling complexes called BAF complexes and their role in gene regulation.

The genomic sequencing projects from the last decade have brought BAF complexes to the forefront of attention, owing to the fact that they are mutated in over 20% of human cancers. Dr. Kadoch tells GEN that “it was a very surprising and exciting discovery that perturbed BAF complexes were major drivers of cancer, given that for years, BAF complexes had been thought to mainly serve maintenance functions in the cell.”

Today, perturbed BAF complexes seem to be one of the biggest culprits in cancer. Indeed, “they are the most frequently mutated chromatin regulator in all of human cancer,” asserts Dr. Kadoch. In some cancers, such as synovial sarcoma (SS), a rare malignancy, 100% of tumors have a precise translocation involving a specific BAF subunit, SS18, indicating that the translocation is the initiating oncogenic event.

Interestingly, no other mutations are found in these tumors. Mutations in the BAF complex have been found in many pediatric and adult cancers, ranging from rare sarcomas to common cancers such as lung and breast cancers. Unlike HDACs and polycomb complexes, to date, there are no agents in the clinic targeting BAF complexes. Dr. Kadoch says that it is “an unmet need.”

With a desire to see her laboratory’s discoveries translated into new medicines, Dr. Kadoch founded Foghorn Therapeutics to “hunt for drugs.” The company, which has raised $50 million from Flagship Ventures, plans to introduce drugs to the clinic by 2020. It will work on both cancer targets and the other diseases in which BAF complexes have been implicated, including autism spectrum disorder and intellectual disability syndromes.

The power of epigenetics in drug discovery is only beginning to be uncovered. The last two decades of basic research and the tools that have come out of the genomic revolution have positioned epigenetics at the forefront of novel treatments for cancer and other diseases. As Dr. Cavalli tweeted, “Is there anything really beyond epigenetics? Epigenetics is like the Pillars of Hercules: Sailors who try to go beyond sink into the realm of Atlantis and are lost forever…”.

Previous articleChronic Back Pain Linked to Three Genetic Variants
Next articleNovel Method Improves Imaging and Progression of Atherosclerotic Plaque