Epigenetics and diseases

In 1996, two identical monozygotic twins carrying the same mutation in a region of the X chromosome, developed different disease outcomes. Only one of them developed blindness, balance problems and loss of myelin in the brain: all manifestations of the neurological disease adrenoleukodystrophy (ALD). At the time, the researches reporting the case concluded that non-genetic factors must have been the caused for the different ALD phenotypes. It is nowadays known that this was indeed true and that the causes resided in the different epigenomes of the twins.

Similar cases have been reported after this. Due to the many roles of epigenetics in regulating the expression of genes, its implication in numerous diseases is not surprising. Because epigenetics can silence or boost the expression of “good” and/or “bad” genes, epigenetic defects can be associated with or cause maladies such as cancers, autoimmune diseases, metabolic syndromes, neuropsychiatric disorders or even asthma and (cardio)vascular diseases. In the next lines, we exemplify some of these cases.

Genomic imprinting is an epigenetic mechanism that defines whether the maternal or the paternal copy of a gene will express in a offspring. In each generation, the parent-specific imprinting marks have to be erased, reset, and maintained. If one of the copies is “turned off” and the other copy is defective (due to a mutation, for example), the individual can suffer serious consequences. A number of diseases and disorders have been linked to genetic imprinting; for example, Angelman syndrome, Prader-Willi syndrome and Beckwith-Wiedemann syndrome.

Another group of epigenetically-linked diseases is caused by mutations in proteins that are essential for chromatin modification. These proteins are directly involved in the posttranslational modification of histones and in the methylation of DNA or as readers of these modifications. For example, mutations in the histone acetyltransferases, CREBBP and EP300, are associated with the Rubinstein-Taybi syndrome. Mutations in the genes DNMT3B and ZBTB24, which are required for DNA methylation, lead to Immunodeficiency-centromeric instability-facial anomalies syndrome. And mutations in the histone modification reader, MECP2, causes Rett syndrome.

A number of epigenetic biomarkers are associated with cancers and are employed for different clinical applications. For example, CpG methylation, at a panel of genomic sites, have been used preclinically to classify subtypes of gastric cancer and subtypes of colorectal cancer. DNA methylation at specific genes, such as BMP3, NDRG4, SEPT9, have been approved by the FDA as markers for the diagnosis of colorectal cancer. For diagnosis of pancreatic cancer, histone markers have been used preclinically; for example, H3K4 dimethylation, H3K9 acetylation and H3K27 trimethylation.

In Neurology, a number of epigenetic markers are in preclinical phase. For example, the methylation of the SNCA gene for diagnosis of Parkinson and the trimethylation of H3K9 for the diagnosis of Alzheimer. Or the metylation of the genes APP, BACE1, LRP1 and SORL1 for prognosis of Alzheimer disease.

In autoimmune disorders, epigenetic markers may be used in the future for disease prognosis. For example the methylation of interferon and interleukin genes is used for the prognosis of Lupus.

Epigenetics are also asociated with metabolic disorders such as Type 2 Diabetes and Obesity. Diet can highly influence our epigenetics. Read more about it here.

As mentioned above, identifying the particular epigenetic markers associated with certain diseases can provide means for diagnosing, monitoring and developing interventions that may decrease the risk or the burden of the disease. At EpiQMAx, we help the pharmaceutical industry in discovering novel epigenetic biomarkers and in assessing the effect of drugs and treatments on the epigenetics of individuals.

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