At the 2021 Advances in Genome Biology and Technology meeting, John Greally gave unusual advice regarding confounders in epigenomic studies.
Epigenomics, he told the audience in his talk on âThinking Beyond Creode: Epigenomics and Human Diseaseâ, holds great promise for understanding the genomic mechanisms of disease. “But maybe not the way we think it is.”
The term “creode” was the first word used to define the developmental path taken by different cells and to explain how radically different cells could come from the same source during embryonic development. Biologist CH Waddington, who first coined the term, was trying to explain the influence of genetic variation on the condition of cells.
Today, a major explanation for variations in cellular state is that epigenetic markings affect the ability of the transcription machinery to reach a given piece of DNA. These accessibility differences affect which genes are expressed in a cell and, therefore, what type of cell it is. The experiment can modify the epigenetic constitution of a cell and the epigenetic marks can be inherited, which would explain the multigenerational effects of environmental exposures.
Methylation, however, which is a frequently studied epigenetic marker, can be much more dynamic than this view allows. Greally said some epigenetic markers such as polycomb and heterochromatin changes appear to be much more stable than methylation and could be specific epigenetic inheritance mechanisms.
And epigenetic changes don’t necessarily mean that an individual cell has changed state – that the cells “were sitting in Waddington’s creode, and now epigenetics caused them to sit in another creode,” he said. he declared.
Greatly spoke about changes in the proportion of cell subtypes, transcription factor binding, and DNA polymorphisms as possible confounding factors that can cause, rather than be caused by, changes in DNA methylation.
Greally’s central argument, however, was that “confounders” are also a source of information, rather than a nuisance.
âWe can either try to clean our data and get rid of all of these confounding influences, or, and I would say that’s the most productive approach, take these confounding influences,â said Greally, professor of genetics, medicine. . and pediatrics at the Albert Einstein College of Medicine.
“Yes [you] see that there are changes in cell subtypes that explain the differences between your cases and your controls … you have found something that is relevant to the pathogenesis of the disease, âhe said. overview of cell signaling pathways and sequence polymorphisms.
“We should reap these confounding factors,” he said.
He gave examples for each approach – a study using an epigenomic approach to identify altered proportions of immune cells in patients with lupus, and other identified transcription factors that could be used to recreate a niche in the bone marrow. for hematopoietic stem cells.
The widely predicted approach would be “particularly successful” is to use epigenomic assays to reveal sequence variation. As an example, he described the research published by Melina Claussnitzer of the Broad Institute and her colleagues in the March 2, 2021 print issue of Cell metabolism.
In their study, the researchers identified a regulatory subunit, rs56371916, which altered the binding affinity of the transcription factor SREBP1. This altered binding affinity specifically impacted the expression of ADCY5, which encodes the metabolic enzyme ADCY5, by “changing the chromatin landscape from ready to repressed”. In their work, Claussnitzer and colleagues showed that one of the consequences of the variant was that it affected the efficiency with which progenitor cells differentiated into osteoblasts, specialized cells that break down bone. These findings could explain the link of ADCY5 to osteoporosis and serve as an important reminder that a relationship between epigenetics and outcome does not necessarily mean that there is a mediating change in cell fate.
âIn the area of ââepigenetics, we’re looking at things like exhibits and behavioral and phenotypic outcomes and molecular outcomes,â Greally said. “What we tend to forget to do is look at the actual fabric.”
While rs56371916 is a relatively common variant in East Asian populations, Greally said where the epigenomic approach can really shine is in understanding the function of ultrarare variants.
The functional effects of rare variants identified in population genomics can be difficult to determine, as they are often found in a single individual or family, and are likely to be heterozygous.
But “multiple rare variants can have the same result on DNA methylation or chromatin structure and show allelic effects on one allele over the other,” Greally said, meaning he is possible to use epigenomic assays like “convergent molecular reading of a lot of different variants … This is potentially the most powerful thing we will be able to do with epigenomic assays in the next few years.”