EPIGENETIC DISEASE AND EPIGENETICALLY ENGINEERED MODELS

and EPI-MUTATIONS of EPIGENETIC DISEASE represent a a much bigger universe of discovery. That is, there is but one GENOME in each your cells, but each one has a unique EPIGENOME. All of the potential modifications and combinations of modifications to to this EPIGENOME are infinite, but this is how cells finely regulate GENOME presentation. This simply means that scientists require sequencing technology to analyze millions of EPIGENOMES across a range of diseases, and complex algorithms and artificial intelligence to sort through this insane quantity of data. Fortunately, these tools actually exist and are being expanded rapidly. 

Scroll down to learn about real examples of EPIGENETIC DISEASE. It may be helpful to first learn about basic features of an EPIGENOME, and concepts of EPIGENOME ENGINEERING first.

CANCER

The image to the right displays a recent cancer study out of City of Hope and Texas Tech. Without going into details, scientists were able to introduce and prevent lymphoma. DNA methylation signatures in the liver, elevated over the developmental HOX cluster, clearly demonstrate the presence of cancer in circulation.

http://www.pnas.org/content/early/2018/03/22/1719586115

We see this in human samples again and again. Virtually every EPIGENETIC feature is altered in cancer. Some are specific to cancer type and often involve EPIGENETIC silencing of specific tumor suppressing genes. In short, the EPIGENOME itself is hijacked by cancer to continually access pro-survival genome information and suppress pro-death information. 

Crude global EPIGENOME modulators were among the first successful anti-cancer drugs. It was DNA methylation inhibitor, 5 azacytidine that was first noted to improve leukemia survival in mice in 1964 (Sorm and Piskala) and this compound is still used effectively today. The issue as with most chemotherapies is specificity. It is often unclear which genes 5 aza is altering and side effects from off-targeting to healthy cells can be terrible. 

DIABETES

EPIGENOME studies have revealed, much like cancer, that epigenetic dysregulation is a hallmark of Diabetes. Further for Diabetes, and many of the other candidate Epigenetic diseases listed here, the disease incidence is often different among identical twin sets, which implies epigenetic origins. In both type I (autoimmune) and type II (lifestyle) Diabetes histone modification profiles and DNA methylation are altered genome-wide. Site-specific DNA methylation changes imply epigenetic dysfunction in autoimmunity as well as glucose sensing and handling pathways in multiple tissue types. Researchers are even beginning to understand that long-term Diabetic complications can be linked to persistent EPIGENETIC "MEMORIES," that may heighten complications. 

http://www.pnas.org/content/113/21/E3002/tab-article-info

HEART DISEASE

Cancer, Diabetes, cardiovascular complications, and heart disease are all interconnected. Therefore, there are common epigenome dysregulation markers and these often reflect persistent stress or DNA damage brought on by the disease or related therapies. 

At the molecular level, heart failure is often marked by irregular calcium signaling with contractile cells (cardiomyocytes), disrupted excitation- contraction coupling, increased hypertrophy signaling, impaired β-andrenergic responses, altered cell death and developmental, gene expression. In fact, it appears as though many fetal genes are EPIGENETICALLY re-expressed in heart failure. 

In heart disease, contractile cells are generally incapable of dividing and can not regenerate following a major heart attack or during progressive heart failure. Therefore, this disease like many others requiring cell replacement therapies, is a good target for stem cell based regenerative medicine. Though new cells can be used for transplant (active research area), by modeling epigenetic features of development, researchers may be able to use this information to epigenetically turn adult heart cells into those capable of regeneration. 

https://link.springer.com/article/10.1007%2Fs11515-014-1340-0

IMPRINTING DISEASES

Prader-Willi syndrome represented the first report of an IMPRINTING DISEASE, due to a paternal deletion of chromosome 15. Later, similar genetic changes were reported Angelman syndrome. Imprinting is a bit complicated, but in short  imprinted genes are expressed from from only one allele (you have a 2 for each gene, one from each parent). These rare genes, are expressed in an EPIGENETIC manner in gametes, where only one copy or "MONOALLELIC EXPRESSION" should occur. DNA methylation is especially important for proper imprinting. In a very recent report, imprinting could be corrected in a stem cell model of Angelman syndrome. This proof-of-prinipal raises prospects of correcting such EPIGENETIC diseases.    

http://science.sciencemag.org/content/356/6337/503.long 

NEUROLOGICAL CONDITIONS

Besides imprinting disorders, which typically involve some cognitive developmental delays, a number of other EPIGENETIC neurological disorders exist. Brain developmental is amazingly complex and involves the differentiation of dozens of neuron types and even more subtypes overtime. We now understand that actual memories are in part epigenetically stored. Therefore, it should not be surprising that a number of neurological conditions have epigenetic origins. With new global sequencing efforts, it has become apparent that disease risk sequences for autism and schizophrenia lie outside of protein-coding genes. 

Researchers are still discovering EPIGENETIC features of neurological disease, but dysregulation has already been detected in classic diseases such as Alzheimer's, Parkinson's, epilepsy, and others. As the underlying genes involved are often unique as is the underlying epigenetic changes. With new EPI-EDITING TOOLS, however, finally new, previously unattainable disease models can be generated. 

RETT SYNDROME

Sometimes the EPIGENETIC disease has more to do with the protein reading the EPIGENOME than a problem with an epigenetic mark itself. In Rett syndrome, researchers discovered mutations in Methyl DNA binding protein MECP2. This didn't alter the DNA methylation patter, but it did result in inappropriate or a total lack of MECP2 binding to methylated DNA. Without this binding, proper DNA looping can not form with other DNA binding factors and gene regulation of key genes, especially those in neurological development, can not be maintained. The result is a progressive decline from initially loss of motor control and jerky limb movement to cognitive decline, intellectual disabilities, and seizures, among other symptoms. 

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett-Syndrome-Fact-Sheet

In the future, researchers will have a more comprehensive understanding of EPIGENOME DYSREGULATION and the origins of EPIGENETIC DISEASES like those listed above. With this knowledge, new EPI-DISEASE models can be generated and targeted or BIOMARKER specific EPIGENETIC THERAPIES  developed. 

Finding EPIGENETIC disease targets can be complex, but new technologies have enabled genome-wide EPIGENETIC MAPS to be generated and analyzed. For some diseases, their unique EPIGENOME may be exploitable for therapy. Once we have a target, we can begin to check for disease features in cell line and animal models and test new therapies. 

Some of the latest and greatest new EPI-DISEASE modeling examples are described below:

"In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation." This paper describes the use of activating dCas9 in vivo to activate target genes needed to alleviate a number of disease symptoms in mouse models. By choosing key genes to epigenetically activate, these researchers were able to  treat mice with Diabetes, muscular dystrophy, and acute kidney disease. 

https://www.cell.com/cell/fulltext/S0092-8674(17)31247-3

Total CG island methylation technology allows modeling and correction of Angelman syndrome in induced pluripotent stem cells (iPSCs). 

In this recent science article, researchers were able to induce targeted DNA METHYLATION at an defective IMPRINTING loci to restore proper gene expression. 

https://www.ncbi.nlm.nih.gov/pubmed/28473583

"Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice." This recent study demonstrates epigenetic editing in an Alzheimer's mouse can alleviate symptoms. This also highlights that Cas9 need not be the Homing enzyme for EPIGENETIC EDITING CARGO (they used zinc fingers). 

https://academic.oup.com/brain/article/140/12/3252/4632922

Insect epigenetic models may offer insight into a number of human pathologies. Some of our essential EPIGENOME regulating mechanisms are conserved across species and even in insects. Similar developmental pathways are at work in aging and in cancer development and these studies often yield the most promising targets to follow-up with in mammalian studies. These and other organisms such as zebrafish can be used to model epigenetic responses to radiation treatment. 

https://www.sciencedirect.com/science/article/pii/S0079610715000346

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