Breaking the Code: Unlocking the Secrets in the Human Epigenome

As science has progressed, more research has uncovered the secrets locked within the human epigenome. Could new treatments and possible cures for a variety of endocrine disorders be the next discoveries?

There was a time when mapping the human genome seemed like an impossible task. Yet, through a vast collaborative effort that took 13 years, the Human Genome Project managed to sequence an impressive 99% of the human genome’s gene-containing regions — marking one of mankind’s greatest scientific achievements.

As genetic research and therapies continue to advance at a tremendous pace, scientists have once again started looking to the future for the next great breakthrough. A growing number of experts believe they have found an even larger and more ambitious undertaking, one with enormous implications for the health and well-being of the world’s population: the epigenome.

Rather than operating on a consistent code, epigenetics focuses on alterations and variability in DNA transcription and gene expression that could be influenced by everything from the climate in which one lives to the diet of their ancestors. The dynamic nature of the epigenome makes it an incredibly complex puzzle to decode — a challenge that was unfathomable until several years ago.

The Roadmap Epigenomics Project

The advent of better tools and technology, combined with growing collaboration between the dominions of computer science and medical research, has brought a map of the epigenome into the realm of possibility.

A consortium of North American scientists recently completed the Roadmap Epigenomics Project — a NIH-funded inquiry — into the epigenetic mechanisms that shape the human body and also result in many of our ailments. The researchers analyzed 150 billion sequencing reads, which is a feat equivalent to about 3,000 times the coverage of the human genome. These reads were taken from different antibodies and cell types and translated into a meaningful annotation of 111 primary cell and tissue types.

This data culminated in 24 coordinated publications in Nature and other Nature journals, including an integrative analysis paper spanning the completed dataset.

“The field has made tremendous progress over the last few years,” says Manolis Kellis, PhD, a professor of computer science at MIT, Cambridge, Mass., and the leader of this integrative analysis.

Kellis’ team of bioinformatics experts developed algorithms that learn the patterns of behavior in the chemical modifications on DNA, as well as the histone proteins that the DNA wraps around. These chemical signatures were then systematically mapped across a spectrum of cell types.

“We’ve been able to elucidate the chemical signatures associated with different types of elements — promoter regions, enhancer regions, repressor regions, and so on,” Kellis explains.

By decoding these regulatory elements, researchers are able to use genomic association studies to uncover the locations where epigenetic variation is associated with disease.

The data was collected by a cooperative of mapping centers across the U.S. and Canada, and is being used for a variety of different purposes. It operates as a public database of epigenetic findings that can be searched, visualized, and extracted.

What is Epigenetics?

Like control dials on our DNA, epigenetic marks direct the activity level of genes. This can mean differentiating cell types, like instructing a cell to become a liver cell instead of a heart cell, or controlling the genes that regulate the development of certain diseases.

“Genes need a specific epigenetic program to function properly,” explains Moshe Szyf, PhD, Professor of Pharmacology at McGill Medical School in Montreal, Quebec, and a pioneer of epigenetic research, who was not involved in the Roadmap Epigenomics Project. “The same gene can work differently in response to different signals, or might be completely silent in some cells but highly active in others.”

The implications of this are far reaching. Szyf believes that the epigenome plays some role in almost every single disease in existence. He has studied the ties between epigenetics and cancer, and more recently the relationship between behaviors and epigenetics.

There is growing evidence that the behaviors and environmental exposures of parents, and even grandparents, affect the development and health of individuals on an epigenetic level. This implies that inheritance happens through more than just genetic code; we may also inherit past generations’ experiences in the form of epigenetic marks.

Szyf is currently investigating how behaviors like cocaine addiction are related to epigenetics, in addition to experiments involving post-traumatic stress syndrome and prenatally stressed mothers and their children. He is also researching how DNA methylation — a primary building block of epigenetics — may be used as a marker of cancer progression.

The Secrets of Cell Differentiation and Regulation

One of the main goals of the Roadmap Epigenomics Project is to elucidate the inner workings of our cells. The actual differences between cell types have remained somewhat mysterious despite the many scientific advances made over the ages. By mapping the epigenome, researchers have been able to isolate the regulatory regions on our DNA that determine this across the 111 cell types included in the project.

“It is generally not known which regulators control what tissues and what genes are controlled together,” says Kellis. “We exploited the dynamics of the epigenome to actually link together modules of regulatory regions that act in coordination and discover regulatory patterns that appear extreme, implying that they could be controlling these regions.”

Researchers are now using this information to further our understanding of the circuitry of human cells and the molecular basis of human disease.

The Role of Methylation

Methylation describes the addition of a methyl group to a protein or strand of DNA, thereby altering gene expression and transcriptional activity. When cancer develops, the genes that promote cancer become unmethylated and genes that suppress cancer become methylated. This process can similarly cause stimulation or suppression of countless other diseases.

“The big question is: why do changes in methylation from the ‘normal’ program of DNA methylation happen?” Szyf posits. “Is it just an accident? Or is it the response to an experience or an exposure?”

The chemical interactions that cause changes in DNA methylation are not well understood. However, if scientists can isolate environmental factors that cause variation in epigenetic marks, they might be able to find prevention strategies for some illnesses. “I think that’s where epigenetics will make its biggest contribution: By tying together the environment and disease,” Szyf says.

Some factors, like smoking and exposure to certain chemicals, have become well-recognized modifiers of DNA methylation, but the data is still sparse on a long list of other possible factors.

Epigenetic Influence

So far, the Roadmap has helped researchers discover patterns that explain the origins of phenotypes ranging from height and cholesterol levels to ADHD and multiple sclerosis. The results have often been surprising.

It is widely known that Alzheimer’s disease is associated with neurodegeneration, which is accompanied by inflammation. This inflammation has always been considered a consequence of the neurodegenerative process. But the genetic variants that predispose individuals to Alzheimer’s disease are not localized in the control regions of the neurons that die — instead, they are localized in the control regions of immune cells. This suggests that the inflammation may actually be driving neurodegeneration rather than the reverse.

Kellis hopes that the Roadmap will also catalyze the development of many medical applications for epigenetics. Progress in cancer diagnosis is picking up speed, and he anticipates that oncologists will soon be able to use epigenetic marks to find the source of metastatic cancers with unknown origins in the body.

Szyf agrees. “I think the diagnostic DNA methylation marker market is going to explode,” he says. “It will provide exquisite tools to differentiate both in mental health and physical health like cancer, diabetes, stages of different kinds of diseases as well as predict diseases.”

Epigenetic Therapies

In addition to diagnostic and predictive potential, epigenetic therapies are also in development. The U.S. Food and Drug Administration has approved several already, most recently a drug called panobinostat for the treatment of multiple myeloma. Panobinostat blocks a harmful enzyme that can change the epigenetic properties of DNA, thereby inhibiting the growth of the cancer.

A new study published in Nature Medicine shows that panobinostat slows the growth of DIPG —a fatal form of brain cancer that takes the lives of hundreds of children in the U.S. each year. The study implanted tumors into mice and found that the drug increased survivability. Although still in preclinical stages, the drug shows potential as a therapy for patients with this devastating diagnosis.

Szyf predicts that epigenetic therapies will be created for a wide range of diseases — from Alzheimer’s to schizophrenia to diabetes and beyond. “Drug development is still moving very slowly,” he says, “but, at some moment, there is going to be an inflection and epigenetic treatments will exponentially explode.”

Kellis encourages cautious optimism when it comes to finding epigenetic cures for diseases, though. “We get very excited when a correlation with a disease is found, but it’s often unclear whether that epigenetic variation is the cause of the disease or simply the consequence of the disease.”

For diseases that have epigenetic variation as a symptom instead of a cause, epigenetic therapy is probably not in the cards. Yet, the epigenome still contains many discoveries that are waiting to be made.

—Mapes is a Washington D.C.-based freelance writer and a regular contributor to Endocrine News. She wrote about the artificial pancreas in pediatric patients in the May issue.


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