Thirty years ago, many scientists believed that mapping the human genome would be the key to ending all diseases. We now know that genetics is more complicated than we first anticipated. This understanding has steered many researchers to look beyond the genome to study what lies “on top” of the DNA, better known as epigenetics. However, this field is very new and mostly uncharted, and despite overwhelming interest, there is still much to learn.
The primary challenge at present is that unlike the genome, which is identical in every cell, the epigenome differs across cell and tissue type. Perhaps, if researchers knew which genes to explore, it might advance their progress. This undertaking is exactly what a team from Baylor College of Medicine and Texas Children’s Hospital hope to achieve. Their latest study featured in Genome Biology presents what might be considered a “treasure map” for epigenetics and human disease.
Epigenetics is the study of modifications that occur to gene expression that do not alter the underlying nucleotide sequence. Chemical reactions brought on by molecular marks that attach to DNA determine whether a gene is turned on or off. These marks essentially instruct a cell what to be (skin, blood, bone, etc.) and how to perform. Whereas a person’s genotype can be determined from sampling any tissue, epigenetic regulation is cell-specific. A blood cell, for instance, can’t convey what kind of molecular dysregulation is going on in another part of the body.
Or, maybe it can. According to Robert A. Waterland, Ph.D., Professor of Pediatrics-Nutrition at Baylor College of Medicine and his team, a blood sample could be used to surmise epigenetic regulation throughout the body – it’s just a matter of looking at specific regions in the genome to find those clues.
The focus for the assessment was DNA methylation because it is a stable repressive mark and well regarded for its vital role in epigenetic silencing of transcription. In previous studies, we have addressed how this extra methyl group fixed to DNA can affect changes that occur during embryo development, which can then impact future health. We’ve also reported on how blood samples measuring DNA methylation can be used to detect diseases like pancreatic cancer and type 2 diabetes.
The team performed genome-wide DNA methylation analysis of the thyroid, heart, and brain from 10 cadavers. They were then able to identify the genomic regions in which DNA methylation varies between individuals but remains constant throughout tissues.
“Since these tissues each represent a different layer of the early embryo, we’re essentially going back in time to events that occurred during early embryonic development,” said Prof. Waterland, who converted methylation data into a genetic signal to map DNA methylation with his group, then sequenced the genomes. “Our atlas required massive amounts of sequencing data — 370 times more than were used for the first map of the human genome in 2001.”
Their method identified 9,926 correlated regions of systemic interindividual variation (CoRSIVs). Although these previously unknown regions represent just 0.1% of the human genome, the researchers report that it’s possible for CoRSIV methylation in one tissue to detect the expression of associated genes in another.
According to Cristian Coarfa, Ph.D., co-leader of the project and associate professor of molecular and cell biology at Baylor. “Recent studies are already showing that methylation at these regions is associated with a range of human diseases including obesity, cancer, autism, Alzheimer’s disease, and cleft palate.”
The researchers believe that their findings should aid other epigenetic studies concerning human diseases. Waterland points out that epigenetic markings have the power to establish certain genes as either active or inactive. “Any disease that has a genetic basis could equally likely have an epigenetic basis,” he noted. “There is incredible potential for us to understand disease processes from an epigenetic perspective. CoRSIVs are the entryway to that.”
Source: Gunasekara, CJ et al (2019) A genomic atlas of systemic interindividual epigenetic variation in humans. Genome Biology 2019 20:105.
Reference: Homa Shalchi, A treasure map to understanding the epigenetic causes of disease. Baylor College of Medicine. Jun 3, 2019.